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Interleukin 18 in the CNS

Silvia Alboni, Davide Cervia, Shuei Sugama and 1 more

Journal of Neuroinflammation · 2010 · Review

doi:10.1186/1742-2094-7-9

Abstract

Interleukin (IL)-18 is a cytokine isolated as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, the localization of the IL-18 receptor complex in neurons and the neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Interleukin (IL)-18 was isolated in 1995 as a co-factor that, in synergism with IL-12, stimulated the production of gamma interferon (INF-γ) in Th1 cells. Since then extensive in vitro and in vivo studies have identified IL-18 as an important link between innate and adaptive immune responses and a regulator of both cellular and humoral immunity. Constitutively produced as an inactive precursor by several cell types IL-18 is secreted in its active form following maturation by caspase 1 in response to inflammatory and infectious stimuli. In addition to its effects on Th1 cells, IL-18 is a strong stimulator of the activity of natural killer cells alone or in combination with IL-15, and of CD8+ lymphocytes. Together with IL-2, IL-18 can also stimulate the production of IL-13 and of other Th2 cytokines. Thus, it is perhaps not surprising that IL-18 was found to be associated with or demonstrated to contribute to numerous inflammatory-associated disorders. These include infections, autoimmune diseases, rheumatoid arthritis, cancer, as well as metabolic syndrome and atherosclerosis.

2IL-18 had not originally been expected to cross an intact blood brain barrier and its immunological effector cells are not normally found in the healthy brain. Yet, studies on the possible role of IL-18 in the central nervous system (CNS), initiated soon after its cloning, were prompted primarily by its similarities with IL-1, which was already demonstrated to have central action. It was soon found that IL-18 could be synthesized centrally and its receptor subunits were now demonstrated to be broadly expressed in neurons. When recombinant interleukin 18 became available it also became clear that IL-18 was active centrally. Work on mice null for IL-18 or its receptor subunit alpha is helping to decipher the action of this cytokine in the brain. Finally, the recent discovery of novel IL-18 receptor subunits in the brain has revealed the complexity of the IL-18 system and may lead to better understanding of both the similarities and opposing actions of IL-1 and IL-18. This review summarizes more than a decade of work aimed at understanding how the IL-18 system contributes to local central inflammatory processes or can influence neuronal function and behavior. A summary of the literature supporting the involvement of IL-18 in neurophysiological and neuropathological conditions is presented in Table 1.

Components of the IL-18 system

3IL-18 is synthesized as an inactive 24-kDa precursor protein that is subsequently processed by caspase-1 into its mature secretable form, which has a molecular weight of 18 kDa. Pro-IL-18 can also be processed into its active form by various extracellular enzymes including protease 3 (PR-3), serine protease, elastase and cathepsin G. Only the mature peptide is reported to be biologically active.

4The existence of a putative short isoform of IL-18 resulting from alternative splicing removing 57 bp/19 aa was first described in rat adrenal glands (IL-18α) and subsequently in mouse spleens (IL-18s). Recombinant IL-18s did not display IL-18-like activity in stimulating INF-γ production when tested alone but appeared to have a modest synergistic action with IL-18. To this date this isoform has not been reported in the CNS.

5The IL-18 receptor (IL-18R) belongs to the interleukin 1 receptor/Toll like receptor superfamily. It is comprised of two subunits, IL-18Rα (also known as IL-1Rrp1, IL-18R1 or IL-1R5) and IL-18Rβ (also termed IL-18RacP, IL-18RII or IL-1R7) both with three extracellular immunoglobuling-like domains and one intracellular Toll/IL-1 receptor (TIR) domain. IL-18 is believed to bind directly only to IL-18Rα with signal transduction occurring after recruitment of IL-18Rβ to form a high-affinity heterotrimeric complex with IL-18Rα/IL-18.

6Isoforms of both IL-18Rα and IL-18Rβ were recently described in vivo in the CNS. They include a short transcript for IL-18Rα encoding for a receptor subunit lacking the TIR domain arbitrarily named IL-18Rα type II. Since the TIR domain is required for signaling, IL-18Rα type II was proposed to be a decoy receptor, similar to the type II IL-1R. In addition, a truncated form of IL-18Rβ comprising only one of the three immunoglobulin domains was described in rat and human tissues including the brain. This form was proposed to act as a soluble negative regulator of IL-18 action by stabilizing IL-18 binding to IL-18Rα yet preventing signaling.

7Another negative regulator of IL-18 action is the IL-18 binding protein (IL-18BP). Isolated as cytokine-binding molecules, this 38-kDa soluble protein displays some sequence homology with IL-18Rα. IL-18BP binds selectively and with high affinity to mature IL-18, but not to pro-IL-18, preventing its interaction with IL-18Rα. Four human (18BPa-d) and two murine (IL-18BPc and d) IL-18BP isoforms have been described. Of these human IL-18BPb and d lack the structural requirement to inhibit IL-18 action and their role remains to be determined.

8A different member of the IL-1 family, IL-1F7, is also a negative regulator of IL-18 action. IL-1F7 is able to bind IL-18BP and the IL-18BP/IL-1F7 complex can interact with the IL-18Rβ chain preventing the formation of the funtional IL-18R complex. Several human IL-1F7 splice variants (IL-1F7a-e) have been described whereas no murine homologue of IL-1F7 has yet been found. Of these, IL-1F7b (also known as IL-1H, IL-1H4 and IL-1RP1) matured by caspase-1 is capable of binding IL-18Rα. Yet, the IL-1F7/IL-18Rα complex failed to recruit IL-8Rβ and no direct agonistic nor antagonistic activity of IL-1F7b for IL-18R was described.

IL-18 signaling

9Canonical IL-18 action occurs via recruitment of the adaptor myeloid differentiation factor (MyD88). This event allows activation of the IL-1R-associated kinase (IRAK)/tumor necrosis factor receptor-associated factor 6 (TRAF6) pathway leading to nuclear translocation of the nuclear factor kappa beta (NF-κB) and subsequent modulation of gene transcription (Fig 1).

10IL-18 has also been reported to signal via the activation of the transcription factor tyk-2, STAT3 and NFATc4. In addition, a role for mitogen-activated protein kinases (MAPK) (i.e., extracellular signal-regulated kinase, ERK1/2 and p38), and phosphatidylinositol-3 kinase (Pi3K) in IL-18 signalling has been suggested.

11While these data on peripheral cells were consolidated over a decade of work with the immune system, knowledge of the IL-18-dependent signaling in the CNS is only beginning to emerge. Activation of the IL-18R increased NF-κB phosphorylation and induced hypertrophy in astrocytes. In the rat dentate gyrus, the functional effects of IL-18 were significantly attenuated by prior application of c-jun-n-terminal kinase (JNK) pathway, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) inhibitors, and a role for p38 MAPK was also suggested. Moreover, human neuron-like differentiated SH-SY5Y neuroblastomas exhibited an IL-18-dependent increase in the levels of several kinases including p35, Cdk5, GSK-3beta, and Ser15-phosphorylated p53.

IL-18 system in the CNS

12IL-18 transcript was demonstrated by RT-PCR in a variety of brain regions including the hippocampus, the hypothalamus and the cerebral cortex. In in vivo studies, IL-18 protein was demonstrated in the pituitary gland, ependymal cells, the neurons of the medial habenula (where its synthesis was elevated by stress), in Purkinje cells, and in astrocytes in the cerebellum. In addition, it was demonstrated in vitro that microglia and astrocytes can produce IL-18 and its level can be up-regulated following LPS stimulation or treatment with INF-γ.

13In the CNS, Northern blot analysis failed to detect the presence of IL-Rα and IL-Rβ soon after their cloning. The first evidence that IL-18R components are expressed in brain tissue was obtained by Wheeler and colleagues which reported the constitutive expression of IL-18Rα, IL-18Rβ in the rat hypothalamus by RT-PCR. Subsequently, the mRNA expression of IL-18Rα, IL-18Rβ and the soluble form of the IL-18Rβ were detected in the hypothalamus, hippocampus, striatum and cortex and in cultured astrocytes, microglia and neurons. More recently in vivo analysis showed that IL-18Rα mRNA and protein are constitutively expresseed in neurons throughout the brain. Similar neuronal localization and distribution was found for IL-18Rβ (Alboni et al., unpublished data). At the same time it was demonstrated that the truncated decoy form of the IL-18Rα was expressed in neuronal cells with a pattern similar to that of its active counterpart. Overall, IL-18R subunits had broad distribution across the brain with the highest level in the hypothalamus, hippocampus and amygdala. Finally, both IL-18 and IL-18R subunits are inducible and their CNS levels can be regulated. For instance, in the mouse hippocampus the levels of IL-18 and IL-18Rα increased after kainic acid (KA)-induced excitotoxicity, whereas hypoxic-ischemic brain injury markedly increased IL-18 expression in mouse microglia. In addition nerve injury induced IL-18 upregulation in rat spinal cord microglia possibly via p38 activation.

14IL-18BP has been investigated and demonstrated in rodent brains, mixed glia and microglia by only one group using RT-PCR. Its distribution and action in the CNS remain to be investigated.

15Information on central IL-1F7 is also limited to one study that demonstrated its presence in the human brain. Investigating IL-1F7 in the CNS is also hampered by the fact that a mouse homologue has not been identified.

Behavior

16The similarities between the IL-1 and the IL-18 systems suggested the possibility that like IL-1β, IL-18 may be one mediator of the behavior symptoms of sickness. These include fever, lethargy, hypophagia and cognitive alterations.

17It was demonstrated that central intracerebroventricular (i.c.v.) injection of IL-18 in rabbits and rats increased non-rapid eye movement sleep as well as brain temperature. The lethargic effects of IL-18 were also observed following intraperitoneal injection of IL-18, whereas, unlike IL-1β, peripheral administration did not induce fever. Instead, pre-treatment with IL-18 reduced the pyrogenic effects of IL-1 suggesting the possibility of an antagonizing effect of these cytokines on fever.

18Work on IL-18 null, and on IL-18BP overexpressing mice indicated that IL-18 is anorexigenic and can modulate feeding, but also energy homeostasis, influencing obesity and insulin resistance. The mechanisms through which IL-18 exerts these effects are largely unknown but central action was proposed following the observation that i.c.v. injections of exogenous IL-18 induces sleep and anorexia. The recent demonstration that IL-18 functional and regulatory subunits of the IL-18R are expressed in several brain regions including the hippocampus, the hypothalamus and the cortex provided a molecular and cellular basis for the central action of IL-18 in modulating these functions.

19Evidence for the role of IL-18 as modulator of neuronal functions includes studies on the hippocampal system, a structure that plays a major role in memory and in cognition. For instance, IL-18 reduces long term potentiation (LTP) in the rat dentate gyrus, possibly through the involvement of metabotropic glutamate receptors. In particular, IL-18 had no effect on baseline synaptic transmission or paired pulse depression, but significantly depressed the amplitude of NMDA receptor-mediated field excitatory post synaptic potentials providing evidence of a direct neuromodulatory role for IL-18 in synaptic plasticity. It is possible that IL-18 may act directly on the neurons of the dentate gyrus, moreover, its action may be regulated by the relative level of IL-18Rα type I and type II, both highly expressed in these cells. Work on CA1 pyramidal neurons of mouse hippocampal slices demonstrated that IL-18 stimulated synaptically released glutamate and enhanced postsynaptic AMPA receptor responses, thereby facilitating basal hippocampal synaptic transmission without affecting LTP.

20Recently an ex vivo study found that LPS-induced IL-18 elevation in the brain was unable to affect LTP in the CA1 hippocampal subregion. However, when comparing wild-type and IL-18 KO mice, the same study demonstrated that IL-18 regulates fear memory and spatial learning. In particular, assessment of spatial learning and memory with the water maze test showed that compared to wild-type mice IL-18 KO mice exhibit prolonged acquisition latency and that this phenotype was rescued by i.c.v. injection of IL-18.

Stress and the hypothalamic-pituitary-adrenal axis

21IL-18 occupies a peculiar role in stress response both centrally and peripherally. This subject was recently extensively reviewed and we briefly refer to it here only for those aspects relevant to understanding of the central actions of this cytokine.

22In response to restraint stress, IL-18 null mice showed a markedly reduced morphological microglial activation in the thalamus, hypothalamus, hippocampus, substantia nigra and central gray area. In addition, IL-18 expression was elevated by restraint stress in the neurons of the medial habenula. Since the habenula is a potential site for the interaction of neuro-endocrine and immune functions, the possibility exists that IL-18 might mediate the communication between the CNS and the periphery. Indeed, there is a general agreement that IL-18 may regulate hypothalamic-pituitary axis activity, possibly mediating the stress response of the adrenal gland. In this respect, stress has been shown to induce transient IL-18 mRNA elevation in rat pituitary cells where increase of the IL-18 mRNA level was observed also after adrenalectomy.

23IL-18 is also produced in the neurohypophysis as well as in the adenohypophysis where in situ hybridization combined with immunohistochemistry demonstrated its expression in corticotrope cells. In addition, bovine somatotropes have been shown to produce IL-18 and IL-18Rα was co-localized with IL-18, or growth hormone, suggesting the possibility that IL-18 acts on somatotropes through the autocrine pathway. However, IL-18 seems to also act at the hypothalamic level. Indeed, the application of IL-18 in rat hypothalamic explants decreases basal and KCl-stimulated corticotropin-releasing hormones (CRH), as well as CRH gene expression. In particular, the cytokine did not modify basal PGE2 production but abolished production stimulated by IL-1β demonstrating that IL-18 possesses a profile of in vitro neuroendocrine activities opposed to, and even antagonizing, those of IL-1β. Recently, IL-18 was localized in the marginal cell layer of the bovine and porcine Rathke's pouch, that is assumed to embody a stem/progenitor cell compartment of the postnatal pituitary gland. Interestingly, stimulation of a cloned anterior pituitary-derived cell line (from the bovine anterior pituitary gland) with IL-18 increased expression of mRNAs of a different cytokine suggesting the possibility that IL-18 may modulate not only the immuno-endocrine function of the pituitary cells but also their development.

Microglia and neuroinflammation

24Functional maturation and activation of IL-18 can occur in the brain under inflammatory conditions. Indeed, as extensively reviewed by Felderhoff-Mueser and colleagues, experimental and clinical studies suggest that binding of IL-18 occurs in several neuroinflammatory associated pathological conditions including microbial infections, focal cerebral ischemia, Wallerian degeneration and hypoxic-ischemic, hyperoxic and traumatic brain injuries (e.g., stroke). Further evidence comes from recent papers reporting an activation of IL-18 in the brain of mice that underwent thromboembolic stroke or an increase of IL-18 levels after hypoxia-ischemia in the juvenile hippocampus of mice.

25During CNS inflammation, the IL-18 system may have an important role in the activation and response of microglia and possibly infiltrating cells. As mentioned above, microglia cells can synthesize and respond to IL-18. IL-18 KO mice had impaired microglia activation with reduced expression of Ca2+-binding protein regulating phagocytic functions that resulted in reduced clearance of neurovirulent influenza A virus. In the absence of infection IL-18 deficient mice also showed diminished stress-induced morphological microglial hypertrophy.

26Interestingly, IL-1β is upregulated within 4 h of focal ischemia in rat brain, but IL-18 is upregulated much later, at time points associated with infiltration of peripheral immune cells, thus suggesting different roles for these interleukins in the regulation of glial functions. In this respect, it was shown that mice infected with Japanese Encephalitis produce IL-18 and IL-1β from microglia and astroglia. Both interleukins are capable of inducing pro-inflammatory cytokines and chemokines from human microglia and astroglia, although IL-18 seems to be more potent than IL-1β.

27In the spinal cord, IL-18 seems to play a role in the innate inflammatory response. Indeed, moderate cervical contusive spinal cord injury induced processing of IL-18 in neurons of the rat spinal cord. In addition, nerve injury induced a striking increase in IL-18 and IL-18R expression in the dorsal horn, and IL-18 and IL-18R were upregulated in hyperactive microglia and astrocytes, respectively. Intrathecal injection of IL-18 induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury, suggesting that IL-18-mediated microglia/astrocyte interactions in the spinal cord have a substantial role in the generation of tactile allodynia.

Autoimmune neurodegenerative disease

28A pivotal role for IL-18, in the pathogenesis of autoimmune neurodegenerative disease has been proposed. High levels of IL-18 mRNA were found in the brain and the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Elevated IL-18 transcript was found at the onset and throughout the course of the disease. A different study showed that IL-18 increases severity of EAE. Moreover, it has been demonstrated that anti-IL-18 antibodies or targeted overexpression of IL-18BP in the CNS had preventive effects on the induction of EAE. These observations suggested a role for IL-18 in MS, IL-18 KO mice were susceptible to EAE, whereas IL-18Rα KO mice or IL-18 KO mice treated with anti-IL-18Rα antibodies were not. Thus, alternative IL-18Rα ligands with encephalitogenic properties may exist. In EAE-susceptible Dark Agouti rats, the basal and post-immunization (day 5, 7 and 12) levels of IL-18Rα in lymph node cells were significantly higher than in the EAE-resistant Piebald Virol Glaxo rats.

29In human, serum and cerebrospinal fluid levels of IL-18 are elevated in patients with MS and IL-18 positive cells have been detected in demyelinating brain lesions from MS patients.

30The pathological role of IL-18 in EAE is also supported by the up-regulation of caspase-1 (required to convert IL-18 precursor protein into its biologically active mature form) mRNA in the spinal cord of rats with EAE, and decreased disease severity in caspase-1 KO mice. Finally, peripheral blood mononuclear cells from patients with MS have elevated caspase-1 mRNA levels.

31In addition to a role in MS there is also evidence to support a function for IL-18 in the onset and progression of autoimmune CNS disease. For instance, infection of microglia lines with Theiler's murine encephalomyelitis virus (which causes the development of a chronic-progressive autoimmune demyelinating disease) significantly upregulates the expression of cytokines involved in innate immunity, including IL-18.

Neurodegenerative disorders

32Alzheimer's Disease (AD) is the most common type of human dementia. It is characterized clinically by a gradual but progressive decline in memory and pathologically by neuritic plaques, neuro-fibrillary tangles, and the loss of synapses and neurons. Inflammatory processes were proposed to contribute to neurodegeneration in AD and extensive studies indicated that IL-1 is a pivotal cytokine in mediating direct neuronal loss and sustaining microglia activation leading to further cellular damage in AD. Microglia-derived inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in AD. Increasing evidence indicates that IL-18 may have a role in this scenario.

33For instance, the levels of IL-18 transcript and protein were increased in the frontal lobe of AD patients compared to healthy age-matched controls. In these brains IL-18 was found in microglia, astrocytes and in neurons that co-localize with amyloid-β-plaques and with tau, suggesting that amyloid-β may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction. Additionally, IL-18 can enhance protein levels of Cdk5/p35 and GSK-3β kinases, tau phosphorylation and cell cycle activators in neuron-like differentiated human SH-SY5Y neuroblastoma cells. Thus, on a pathway leading to AD, IL-18 may have an impact on the hyperphosphorylation of tau but also on cell cycle related mechanisms. In the plasma, the levels of IL-18 were significantly elevated in patients with AD, vascular dementia, and mild cognitive impairment compared to the control group. Interestingly, IL-18 levels were higher in AD-mild patients, were slightly lower in AD-moderate patients, whereas no significant difference was observed between AD-severe patients and non-demented age-matched subjects, suggesting a gradual decline of immune responsiveness in AD. Although other studies showed no differences in circulating IL-18 levels measured between AD patients (both mild cognitive impairment and severe AD patients) and controls, a significant increased production of IL-18 was obtained from stimulated blood mononuclear cells or macrophages of peripheral blood of AD patients. Furthermore, a significant correlation between IL-18 peripheral production and cognitive decline was observed in AD patients. Overall, these data indicate that IL-18-related inflammatory pathways, are exacerbated in the peripheral blood of AD patients, and that this cytokine may indeed participate in pathogenic processes leading to dementia.

34Genetic association studies reported that two functional polymorphisms (137G/C and -607C/A) in IL-18 promoter may increase the risk of developing sporadic late onset AD in the Han Chinese population. An association between 137G/C and -607C/A polymorphisms and the susceptibility/clinical outcome of AD was also suggested in an Italian population, although these correlations remain controversial. Indeed, in another Italian population a lack of association between IL-18 gene promoter polymorphisms and onset of AD was reported, indicating that the association of IL-18 promoter polymorphisms with AD is not so strong, AD being a multifactorial disease. Importantly, IL-18 promoter remains poorly characterized.

35Finally, it has been hypothesized that increased production of IL-18 in the brain may lead to motor and cognitive dysfunctions, leading to the development of HIV-associated dementia. Thus, IL-18 concentrations in HIV-infected persons are likely to play an important role in the development and progression of the infection toward AIDS and associated clinical conditions.

36In Parkinsonism, there is evidence of chronic inflammation in the substantia nigra and striatum. Activated microglia, producing proinflammatory cytokines, surround the degenerating dopaminergic neurons and may contribute to dopaminergic neuron loss. In an experimental model of Parkinson's disease that utilized injection of the dopaminergic specific neurotoxin MPTP the number of activated microglial cells in the substantia nigra pars compacta of IL-18 KO mice was reduced compared to wild-type, indicating the possibility that IL-18 may participate in microglial activation and dopaminergic neurodegeneration.

Neuropsychiatric disorders

37Several groups found that depressed and schizophrenic patients have high circulating levels of pro-inflammatory cytokines. Others reported that psychotic episodes often occur in conditions characterized by elevated levels of pro-inflammatory cytokines, for instance during inflammation or in patients suffering from immune diseases.

38Other studies suggested that the correlation between inflammatory markers and psychiatric disorders may be more that merely associative, with inflammation actually contributing to mental disorders. Improvement in psychiatric symptoms has been recently reported in patients treated with anti-inflammatory drugs for other indications and functional allelic variants of genes codifying for pro-inflammatory cytokines were associated with reduced responsiveness to antidepressant therapy. It was also recently demonstrated that IL-6 plays a pivotal role in the pharmacological ketamine model of schizophrenia by modulating the NADPH-oxidase increase of superoxide affecting parvalbumin interneurons. An interesting line of research is exploring the possibility that these actions may be developmental, with cytokines influencing early-life programming of brain functions.

39At present evidence linking IL-18 and psychiatric disorders are primarily associative. IL-18 mRNA expression is elevated in subordinate rat models with depression with respect to dominant rats. A significant elevation of circulating plasma levels of IL-18 has been reported in subjects affected by schizophrenia and were normalized by pharmacological treatment with risperidone, a dopamine antagonist with antipsychotic activity. Normalization was demonstrated also within 6 month of treatment with the antipsychotic clozepine although the possibility that these effects could be due to clozepine's effects on leukocyte numbers cannot be excluded. The serum levels of IL-18 were also significantly higher in moderate-severe depression patients, further suggesting that the pathophysiology of depression is associated with an inflammatory response involving IL-18. Coincidentally, IL-18 is also elevated after stroke, a condition followed by emotional disorders.

40The significance of these correlations with respect to the role of the IL-18 system to neurophsychiatric disease pathophysiology or manifestation remains to be determined. Caution should be taken particularly since peripheral IL-18 can be subject to neurogenic stimulation or stress. It is thus difficult to determine whether IL-18 elevation contributes to these pathologies or whether it is a consequence of the disorders. Indeed, Kokai and colleagues suggest that IL-18 can be considered a psychologic stress-associated marker since they demonstrated that exposure to stressful events (i.e., panic attack in human, restraint stress in mice), the most important precipitating factor in depression, induces a prompt increase in the level of circulating IL-18.

41Regardless, elevated IL-18 levels have the potential to contribute to several of the symptoms associated with neuropsychiatric disorders. For instance, like other pro-inflammatory cytokines, IL-18 may participate in the control of the activity of the HPA axis reported to be dysregulated in depression. IL-18 may antagonize glucocorticoid signalling via activation of NF-κB and p38 MAPK possibly disrupting glucocorticoid-dependent negative feedback on the HPA axis. Finally, IL-18 can affect other hallmarks of depression impairing learning and memory by acting as an attenuator of long-term potentiation, and inducing lethargy and loss of appetite.

Other central actions of IL-18

42Three groups investigated the action of IL-18 in rodents following administration of KA, an agonist of the kainate receptors inducing seizure, cerebellar ataxia and exitotoxic mediated neuronal loss. In mouse hippocampus KA elevated IL-18 and IL-18R expression on microglial cells progressively 3 days after treatment. The authors hypothesized that similar to what was observed peripherally in studies of the immune system, IL-18 may contribute to cellular damage. This hypothesis was partially supported by another group showing that the KA-induced hippocampal neurodegeneration was shown to be more severe in IL-18 KO mice compared to wild-type littermates. Yet, in recombinant mice with the same pre-treatment, IL-18 aggravated both the clinical and pathological signs of neurodegeneration in a dose-dependent manner.

43In the cerebellum, where KA was demonstrate to induce ataxia partially via elevation of IL-1β, exogenous IL-18 was protective and played a positive role in the recovery from kainate-induced ataxia. Consistently, IL-18 KO and IL-18Rα KO mice show delay in recovery from kainate-induced ataxia. The antagonizing effects of IL-18 and IL-1β also observed in the peripheral effects of IL-1β on fever, are intriguing particularly since these cytokines share many similarities including their signalling. Preliminary observations suggest that these effects may be explained by IL-1β and IL-18 targeting different cells or activating distinct signalling.

44Some groups have investigated the possibility that IL-18 could be used against glioma, a common and highly aggressive type of brain tumor with poor long-term prognosis. In this respect, IL-18 was investigated alone or in synergism with IL-12 or Fas, for its ability to induce INFγ and NO inducing a cytotoxic response against glioma cells. Systemic or intracerebral administration of IL-18 inhibited the growth of inoculated glioma cells and prolonged the survival of mice with subcutaneous or brain tumors, respectively. Antitumor activity against glioma was also found in mice treated with IL-18 and IL-12 via Semliki Forest virus or with a combination of IL-18 and Fas. Finally, encouraging data were also reported by overexpressing IL-18 in mesenchymal cells of rats.

Conclusions

45Investigation on the presence of IL-18 in the CNS began soon after its discovery as a co-stimulator of INF-γ production in the immune system. Initially IL-18 was investigated for its similarities with IL-1β as a possible mediator of sickness behavior and of local inflammatory reactions associated with neuronal damage. These actions were both demonstrated and IL-18 was shown to promote loss of appetite, sleep and inhibition of LTP, as well as to be produced by and active in microglial cells, and to possibly contribute to neurodegenerative diseases.

46Yet, two observations suggest that IL-18 has a central role and function that may be unique and distinct from those of IL-1β or other cytokines. The first being the recognition that Il-18 and Il-1β, when their combined action was tested, may have antagonizing effects such as those occurring in fever and in kainate-induced cerebellar ataxia. The second was the finding that IL-18R is constitutively and broadly expressed in neuronal cells throughout the rodent brain. This finding opened the possibility of a direct action of IL-18 on neuronal functions particularly in all of the CNS disorders showed to be correlated to elevated cytokine levels.

47Thus, the investigation of the central action of IL-18 may be considered in its infancy and the significance of the neuronal IL-18R complex and of its isoforms remains to be determined. Among the intriguing peculiarities of the central role of IL-18 is that despite the constitutive expression of the receptor, the regulation of IL-18 action appears to be regulated by the existence of truncated isoforms and by the fact that under normal physiological conditions IL-18 is not easily found in the CNS. Interestingly, the genes encoding for IL-18 and its receptors are subject to differential promoter usage and their transcription to differential splicing indicating that these molecules have the potential of being produced in a tissue/cell specific way in response to different stimuli. It will be important to determine which physiological or pathological conditions modulate these molecules.

48Also unexplored is the investigation of the possible role of IL-18 in CNS development suggested by work on microglial cultures from newborn mice and brain homogenates where IL-18 was preferentially expressed during early postnatal stages and subsequently downregulated, being virtually absent in the brains of adult mice. Additionally, the activated microglia-derived cytokines, including IL-18, may either inhibit the neuronal differentiation or induce neuronal cell death in the rat neural progenitor cell culture, which are cells capable of giving rise to various neuronal and glial cell populations in the developing and adult CNS. Finally, in adult rodents IL-18 is produced in ependymal cells considered a primary source of neural stem cells in response to injury. The possible role of IL-18 in their differentiation has also not been investigated.

49Work on existing IL-18 and IL-18R null mice as well as the development of new experimental models including CNS specific null or overexpressor mice and the identification of suitable in vitro systems will determine the specificity of the central effects of IL-18 in health and disease.

Competing interests

50The authors declare that they have no competing interests.

Authors' contributions

51SA and DC wrote the initial draft of the manuscript, SS and BC contributed to its final version. All authors read and approved the final manuscript.

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Fantuzzi G Puren AJ Harding MW Livingston DJ Dinarello CA Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient miceBlood1998 9121182125
Not in our library
14.
Ghayur T Banerjee S Hugunin M Butler D Herzog L Carter A Quintal L Sekut L Talanian R Paskind M Wong W Kamen R Tracey D Allen H Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma productionNature1997 386619623
Not in our library10.1038/386619a0
15.
Gu Y Kuida K Tsutsui H Ku G Hsiao K Fleming MA Hayashi N Higashino K Okamura H Nakanishi K Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzymeScience1997 275206209
Not in our library10.1126/science.275.5297.206
16.
Ushio S Namba M Okura T Hattori K Nukada Y Akita K Tanabe F Konishi K Micallef M Fujii M Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the proteinJ Immunol1996 15642744279
Not in our library
17.
Fantuzzi G Dinarello CA Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (caspase-1)J Clin Immunol1999 19111
Not in our library10.1023/a:1020506300324
18.
Gracie JA Interleukin-18 as a potential target in inflammatory arthritisClin Exp Immunol2004 136402404
Not in our library10.1111/j.1365-2249.2004.02475.x
19.
Sugawara S Uehara A Nochi T Yamaguchi T Ueda H Sugiyama A Hanzawa K Kumagai K Okamura H Takada H Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cellsJ Immunol2001 16765686575
Not in our library10.4049/jimmunol.167.11.6568
20.
Conti B Jahng JW Tinti C Son JH Joh TH Induction of interferon-gamma inducing factor in the adrenal cortexJ Biol Chem1997 27220352037
Not in our library10.1074/jbc.272.4.2035
21.
Yang YJ Wang ZY Chen SH Ge XR Cloning and characterization of a new isoform of mouse interleukin-18Acta Biochim Biophys Sin (Shanghai)2005 37826834
Not in our library10.1111/j.1745-7270.2005.00116.x
22.
O'Neill LA Dinarello CA The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defenseImmunol Today2000 21206209
Not in our library10.1016/s0167-5699(00)01611-x
23.
Sims JE IL-1 and IL-18 receptors, and their extended familyCurr Opin Immunol2002 14117122
Not in our library10.1016/s0952-7915(01)00306-5
24.
Sergi B Penttila I Interleukin 18 receptorJ Biol Regul Homeost Agents2004 185561
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25.
Thomassen E Bird TA Renshaw BR Kennedy MK Sims JE Binding of interleukin-18 to the interleukin-1 receptor homologous receptor IL-1Rrp1 leads to activation of signaling pathways similar to those used by interleukin-1J Interferon Cytokine Res1998 1810771088
Not in our library10.1089/jir.1998.18.1077
26.
Alboni S Cervia D Ross B Montanari C Gonzalez AS Sanchez-Alavez M Marcondes MC De Vries D Sugama S Brunello N Mapping of the full length and the truncated interleukin-18 receptor alpha in the mouse brainJ Neuroimmunol2009 2144354
Not in our library10.1016/j.jneuroim.2009.06.016
27.
Colotta F Dower SK Sims JE Mantovani A The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1Immunol Today1994 15562566
Not in our library10.1016/0167-5699(94)90217-8
28.
Andre R Wheeler RD Collins PD Luheshi GN Pickering-Brown S Kimber I Rothwell NJ Pinteaux E Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brainJ Neuroimmunol2003 1454045
Not in our library10.1016/j.jneuroim.2003.09.005
29.
Fiszer D Rozwadowska N Rychlewski L Kosicki W Kurpisz M Identification of IL-18RAP mRNA truncated splice variants in human testis and the other human tissuesCytokine2007 39178183
Not in our library10.1016/j.cyto.2007.07.186
30.
Im SH Kim SH Azam T Venkatesh N Dinarello CA Fuchs S Souroujon MC Rat interleukin-18 binding protein: cloning, expression, and characterizationJ Interferon Cytokine Res2002 22321328
Not in our library10.1089/107999002753675749
31.
Kim SH Azam T Novick D Yoon DY Reznikov LL Bufler P Rubinstein M Dinarello CA Identification of amino acid residues critical for biological activity in human interleukin-18J Biol Chem2002 2771099811003
Not in our library10.1074/jbc.m108311200
32.
Novick D Kim SH Fantuzzi G Reznikov LL Dinarello CA Rubinstein M Interleukin-18 binding protein: a novel modulator of the Th1 cytokine responseImmunity1999 10127136
Not in our library10.1016/s1074-7613(00)80013-8
33.
Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18 · 2000
Not checked
34.
Bufler P Azam T Gamboni-Robertson F Reznikov LL Kumar S Dinarello CA Kim SH A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activityProc Natl Acad Sci USA2002 991372313728
Not in our library10.1073/pnas.212519099
35.
Busfield SJ Comrack CA Yu G Chickering TW Smutko JS Zhou H Leiby KR Holmgren LM Gearing DP Pan Y Identification and gene organization of three novel members of the IL-1 family on human chromosome 2Genomics2000 66213216
Not in our library10.1006/geno.2000.6184
36.
Kumar S McDonnell PC Lehr R Tierney L Tzimas MN Griswold DE Capper EA Tal-Singer R Wells GI Doyle ML Young PR Identification and initial characterization of four novel members of the interleukin-1 familyJ Biol Chem2000 2751030810314
Not in our library10.1074/jbc.275.14.10308
37.
Pan G Risser P Mao W Baldwin DT Zhong AW Filvaroff E Yansura D Lewis L Eigenbrot C Henzel WJ Vandlen R IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1RrpCytokine2001 1317
Not in our library10.1006/cyto.2000.0799
38.
Smith DE Renshaw BR Ketchem RR Kubin M Garka KE Sims JE Four new members expand the interleukin-1 superfamilyJ Biol Chem2000 27511691175
Not in our library10.1074/jbc.275.2.1169
39.
Taylor SL Renshaw BR Garka KE Smith DE Sims JE Genomic organization of the interleukin-1 locusGenomics2002 79726733
Not in our library10.1006/geno.2002.6752
40.
Kumar S Hanning CR Brigham-Burke MR Rieman DJ Lehr R Khandekar S Kirkpatrick RB Scott GF Lee JC Lynch FJ Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma productionCytokine2002 186171
Not in our library10.1006/cyto.2002.0873
41.
Dinarello CA Interleukin-18, a proinflammatory cytokineEur Cytokine Netw2000 11483486
Not in our library
42.
Gracie JA Robertson SE McInnes IB Interleukin-18J Leukoc Biol2003 73213224
Not in our library10.1189/jlb.0602313
43.
Shimoda K Tsutsui H Aoki K Kato K Matsuda T Numata A Takase K Yamamoto T Nukina H Hoshino T Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient miceBlood2002 9920942099
Not in our library10.1182/blood.v99.6.2094
44.
Kalina U Kauschat D Koyama N Nuernberger H Ballas K Koschmieder S Bug G Hofmann WK Hoelzer D Ottmann OG IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21J Immunol2000 16513071313
Not in our library10.4049/jimmunol.165.3.1307
45.
Chandrasekar B Patel DN Mummidi S Kim JW Clark RA Valente AJ Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylationJ Biol Chem2008 28342004209
Not in our library10.1074/jbc.m708142200
46.
Fortin CF Ear T McDonald PP Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophilsFaseb J2009 23194203
Not in our library10.1096/fj.08-110213
47.
Miyoshi K Obata K Kondo T Okamura H Noguchi K Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injuryJ Neurosci2008 281277512787
Not in our library10.1523/jneurosci.3512-08.2008
48.
Cumiskey D Pickering M O'Connor JJ Interleukin-18 mediated inhibition of LTP in the rat dentate gyrus is attenuated in the presence of mGluR antagonistsNeurosci Lett2007 412206210
Not in our library10.1016/j.neulet.2006.11.007
49.
Curran BP Murray HJ O'Connor JJ A role for c-Jun N-terminal kinase in the inhibition of long-term potentiation by interleukin-1beta and long-term depression in the rat dentate gyrus in vitroNeuroscience2003 118347357
Not in our library10.1016/s0306-4522(02)00941-7
50.
Ojala JO Sutinen EM Salminen A Pirttila T Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cellsJ Neuroimmunol2008 2058693
Not in our library10.1016/j.jneuroim.2008.09.012
51.
Culhane AC Hall MD Rothwell NJ Luheshi GN Cloning of rat brain interleukin-18 cDNAMol Psychiatry1998 3362366
Not in our library10.1038/sj.mp.4000389
52.
Wheeler RD Culhane AC Hall MD Pickering-Brown S Rothwell NJ Luheshi GN Detection of the interleukin 18 family in rat brain by RT-PCRBrain Res Mol Brain Res2000 77290293
Not in our library10.1016/s0169-328x(00)00069-3
53.
Andoh T Kishi H Motoki K Nakanishi K Kuraishi Y Muraguchi A Protective effect of IL-18 on kainate- and IL-1 beta-induced cerebellar ataxia in miceJ Immunol2008 18023222328
Not in our library10.4049/jimmunol.180.4.2322
54.
Nagai Y Ogasawara H Taketa Y Aso H Kanaya T Miyake M Watanabe K Ohwada S Muneta Y Yamaguchi T Expression of inflammatory-related factors in porcine anterior pituitary-derived cell lineVet Immunol Immunopathol2008 124201208
Not in our library10.1016/j.vetimm.2008.03.007
55.
Nagai Y Ogasawara H Taketa Y Aso H Tanaka S Kanaya T Watanabe K Ohwada S Muneta Y Yamaguchi T Bovine anterior pituitary progenitor cell line expresses interleukin (IL)-18 and IL-18 receptorJ Neuroendocrinol2008 2012331241
Not in our library10.1111/j.1365-2826.2008.01779.x
56.
Sugama S Cho BP Baker H Joh TH Lucero J Conti B Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNSBrain Res2002 95819
Not in our library10.1016/s0006-8993(02)03363-2
57.
Wang N Sugama S Conti B Teramoto A Shibasaki T Interleukin-18 mRNA expression in the rat pituitary glandJ Neuroimmunol2006 173117125
Not in our library10.1016/j.jneuroim.2005.12.009
58.
Conti B Park LC Calingasan NY Kim Y Kim H Bae Y Gibson GE Joh TH Cultures of astrocytes and microglia express interleukin 18Brain Res Mol Brain Res1999 674652
Not in our library10.1016/s0169-328x(99)00034-0
59.
Das S Mishra MK Ghosh J Basu A Japanese Encephalitis Virus infection induces IL-18 and IL-1beta in microglia and astrocytes: correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal deathJ Neuroimmunol2008 1956072
Not in our library10.1016/j.jneuroim.2008.01.009
60.
Jeon GS Park SK Park SW Kim DW Chung CK Cho SS Glial expression of interleukin-18 and its receptor after excitotoxic damage in the mouse hippocampusNeurochem Res2008 33179184
Not in our library10.1007/s11064-007-9434-6
61.
Prinz M Hanisch UK Murine microglial cells produce and respond to interleukin-18J Neurochem1999 7222152218
Not in our library10.1046/j.1471-4159.1999.0722215.x
62.
Sugama S Fujita M Hashimoto M Conti B Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18Neuroscience2007 14613881399
Not in our library10.1016/j.neuroscience.2007.02.043
63.
Suk K Yeou Kim S Kim H Regulation of IL-18 production by IFN gamma and PGE2 in mouse microglial cells: involvement of NF-kB pathway in the regulatory processesImmunol Lett2001 777985
Not in our library10.1016/s0165-2478(01)00209-7
64.
Parnet P Garka KE Bonnert TP Dower SK Sims JE IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcPJ Biol Chem1996 27139673970
Not in our library10.1074/jbc.271.10.5777
65.
Born TL Thomassen E Bird TA Sims JE Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signalingJ Biol Chem1998 2732944529450
Not in our library10.1074/jbc.273.45.29445
66.
Otsuki M Kusumoto K Murakami Y Kanayama M Takeuchi S Takahashi S Expression of interleukin-18 receptor mRNA in the mouse endometriumJ Reprod Dev2007 535968
Not in our library10.1262/jrd.18036
67.
Hedtjarn M Leverin AL Eriksson K Blomgren K Mallard C Hagberg H Interleukin-18 involvement in hypoxic-ischemic brain injuryJ Neurosci2002 2259105919
Not in our library10.1523/jneurosci.22-14-05910.2002
68.
Wheeler RD Brough D Le Feuvre RA Takeda K Iwakura Y Luheshi GN Rothwell NJ Interleukin-18 induces expression and release of cytokines from murine glial cells: interactions with interleukin-1 betaJ Neurochem2003 8514121420
Not in our library10.1046/j.1471-4159.2003.01787.x
69.
Dantzer R Bluthe RM Gheusi G Cremona S Laye S Parnet P Kelley KW Molecular basis of sickness behaviorAnn N Y Acad Sci1998 856132138
Not in our library10.1111/j.1749-6632.1998.tb08321.x
70.
Dantzer R Kelley KW Twenty years of research on cytokine-induced sickness behaviorBrain Behav Immun2007 21153160
Not in our library10.1016/j.bbi.2006.09.006
71.
Dantzer R O'Connor JC Freund GG Johnson RW Kelley KW From inflammation to sickness and depression: when the immune system subjugates the brainNat Rev Neurosci2008 94656
Not in our library10.1038/nrn2297
72.
Kubota T Fang J Brown RA Krueger JM Interleukin-18 promotes sleep in rabbits and ratsAm J Physiol Regul Integr Comp Physiol2001 281R828838
Not in our library10.1152/ajpregu.2001.281.3.r828
73.
Gatti S Beck J Fantuzzi G Bartfai T Dinarello CA Effect of interleukin-18 on mouse core body temperatureAm J Physiol Regul Integr Comp Physiol2002 282R702709
Not in our library10.1152/ajpregu.00393.2001
74.
Cumiskey D Curran BP Herron CE O'Connor JJ A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrusNeuropharmacology2007 5216161623
Not in our library10.1016/j.neuropharm.2007.03.006
75.
Curran B O'Connor JJ The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitroNeuroscience2001 1088390
Not in our library10.1016/s0306-4522(01)00405-5
76.
Kanno T Nagata T Yamamoto S Okamura H Nishizaki T Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slicesBrain Res2004 1012190193
Not in our library10.1016/j.brainres.2004.03.065
77.
Yaguchi T Nagata T Yang D Nishizaki T Interleukin-18 regulates motor activity, anxiety and spatial learning without affecting synaptic plasticityBehav Brain Res2010 2064751
Not in our library10.1016/j.bbr.2009.08.033
78.
Sugama S Conti B Interleukin-18 and stressBrain Res Rev2008 588595
Not in our library10.1016/j.brainresrev.2007.11.003
79.
Sekiyama A Ueda H Kashiwamura S Nishida K Kawai K Teshima-kondo S Rokutan K Okamura H IL-18; a cytokine translates a stress into medical scienceJ Med Invest2005 52Suppl236239
Not in our library10.2152/jmi.52.236
80.
Nagai Y Nochi T Watanabe K Aso H Kitazawa H Matsuzaki M Ohwada S Yamaguchi T Localization of interleukin-18 and its receptor in somatotrophs of the bovine anterior pituitary glandCell Tissue Res2005 322455462
Not in our library10.1007/s00441-005-0016-0
81.
Tringali G Pozzoli G Vairano M Mores N Preziosi P Navarra P Interleukin-18 displays effects opposite to those of interleukin-1 in the regulation of neuroendocrine stress axisJ Neuroimmunol2005 1606167
Not in our library10.1016/j.jneuroim.2004.10.028
82.
Felderhoff-Mueser U Schmidt OI Oberholzer A Buhrer C Stahel PF IL-18: a key player in neuroinflammation and neurodegeneration?Trends Neurosci2005 28487493
Not in our library10.1016/j.tins.2005.06.008
83.
Abulafia DP de Rivero Vaccari JP Lozano JD Lotocki G Keane RW Dietrich WD Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in miceJ Cereb Blood Flow Metab2009 29534544
Not in our library10.1038/jcbfm.2008.143
84.
Qiu L Zhu C Wang X Xu F Eriksson PS Nilsson M Cooper-Kuhn CM Kuhn HG Blomgren K Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemiaJ Cereb Blood Flow Metab2007 27785794
Not in our library10.1038/sj.jcbfm.9600385
85.
Mori I Hossain MJ Takeda K Okamura H Imai Y Kohsaka S Kimura Y Impaired microglial activation in the brain of IL-18-gene-disrupted mice after neurovirulent influenza A virus infectionVirology2001 287163170
Not in our library10.1006/viro.2001.1029
86.
Jander S Schroeter M Stoll G Interleukin-18 expression after focal ischemia of the rat brain: association with the late-stage inflammatory responseJ Cereb Blood Flow Metab2002 226270
Not in our library10.1097/00004647-200201000-00008
87.
de Rivero Vaccari JP Lotocki G Marcillo AE Dietrich WD Keane RW A molecular platform in neurons regulates inflammation after spinal cord injuryJ Neurosci2008 2834043414
Not in our library10.1523/jneurosci.0157-08.2008
88.
Xie WR Deng H Li H Bowen TL Strong JA Zhang JM Robust increase of cutaneous sensitivity, cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal gangliaNeuroscience2006 142809822
Not in our library10.1016/j.neuroscience.2006.06.045
89.
Jander S Stoll G Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis ratJ Neuroimmunol1998 919399
Not in our library10.1016/s0165-5728(98)00162-3
90.
Wildbaum G Youssef S Grabie N Karin N Neutralizing antibodies to IFN-gamma-inducing factor prevent experimental autoimmune encephalomyelitisJ Immunol1998 16163686374
Not in our library
91.
Shi FD Takeda K Akira S Sarvetnick N Ljunggren HG IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-gamma by NK cellsJ Immunol2000 16530993104
Not in our library10.4049/jimmunol.165.6.3099
92.
Schif-Zuck S Westermann J Netzer N Zohar Y Meiron M Wildbaum G Karin N Targeted overexpression of IL-18 binding protein at the central nervous system overrides flexibility in functional polarization of antigen-specific Th2 cellsJ Immunol2005 17443074315
Not in our library10.4049/jimmunol.174.7.4307
93.
Gutcher I Urich E Wolter K Prinz M Becher B Interleukin 18-independent engagement of interleukin 18 receptor-alpha is required for autoimmune inflammationNat Immunol2006 7946953
Not in our library10.1038/ni1377
94.
Thessen Hedreul M Gillett A Olsson T Jagodic M Harris RA Characterization of Multiple Sclerosis candidate gene expression kinetics in rat experimental autoimmune encephalomyelitisJ Neuroimmunol2009 2103039
Not in our library10.1016/j.jneuroim.2009.02.010
95.
Huang WX Huang P Hillert J Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosisMult Scler2004 10482487
Not in our library10.1191/1352458504ms1071oa
96.
Karni A Koldzic DN Bharanidharan P Khoury SJ Weiner HL IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactionsJ Neuroimmunol2002 125134140
Not in our library10.1016/s0165-5728(02)00018-8
97.
Losy J Niezgoda A IL-18 in patients with multiple sclerosisActa Neurol Scand2001 104171173
Not in our library10.1034/j.1600-0404.2001.00356.x
98.
Nicoletti F Di Marco R Mangano K Patti F Reggio E Nicoletti A Bendtzen K Reggio A Increased serum levels of interleukin-18 in patients with multiple sclerosisNeurology2001 57342344
Not in our library10.1212/wnl.57.2.342
99.
Balashov KE Rottman JB Weiner HL Hancock WW CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesionsProc Natl Acad Sci USA1999 9668736878
Not in our library10.1073/pnas.96.12.6873
100.
Furlan R Martino G Galbiati F Poliani PL Smiroldo S Bergami A Desina G Comi G Flavell R Su MS Adorini L Caspase-1 regulates the inflammatory process leading to autoimmune demyelinationJ Immunol1999 16324032409
Not in our library
101.
Furlan R Filippi M Bergami A Rocca MA Martinelli V Poliani PL Grimaldi LM Desina G Comi G Martino G Peripheral levels of caspase-1 mRNA correlate with disease activity in patients with multiple sclerosis; a preliminary studyJ Neurol Neurosurg Psychiatry1999 67785788
Not in our library10.1136/jnnp.67.6.785
102.
Olson JK Girvin AM Miller SD Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler's virusJ Virol2001 7597809789
Not in our library10.1128/jvi.75.20.9780-9789.2001
103.
Caselli RJ Beach TG Yaari R Reiman EM Alzheimer's disease a century laterJ Clin Psychiatry2006 6717841800
Not in our library10.4088/jcp.v67n1118
104.
Griffin WS Inflammation and neurodegenerative diseasesAm J Clin Nutr2006 83470S474S
Not in our library10.1093/ajcn/83.2.470s
105.
Aarli JA Role of cytokines in neurological disordersCurr Med Chem2003 1019311937
Not in our library10.2174/0929867033456918
106.
Ojala J Alafuzoff I Herukka SK van Groen T Tanila H Pirttila T Expression of interleukin-18 is increased in the brains of Alzheimer's disease patientsNeurobiol Aging2009 30198209
Not in our library10.1016/j.neurobiolaging.2007.06.006
107.
Malaguarnera L Motta M Di Rosa M Anzaldi M Malaguarnera M Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer's disease and vascular dementiaNeuropathology2006 26307312
Not in our library10.1111/j.1440-1789.2006.00701.x
108.
Ozturk C Ozge A Yalin OO Yilmaz IA Delialioglu N Yildiz C Tesdelen B Kudiaki C The diagnostic role of serum inflammatory and soluble proteins on dementia subtypes: correlation with cognitive and functional declineBehav Neurol2007 18207215
Not in our library10.1155/2007/432190
109.
Motta M Imbesi R Di Rosa M Stivala F Malaguarnera L Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progressionImmunol Lett2007 1144651
Not in our library10.1016/j.imlet.2007.09.002
110.
Lindberg C Chromek M Ahrengart L Brauner A Schultzberg M Garlind A Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer's diseaseNeurochem Int2005 46551557
Not in our library10.1016/j.neuint.2005.01.004
111.
Bossu P Ciaramella A Salani F Bizzoni F Varsi E Di Iulio F Giubilei F Gianni W Trequattrini A Moro ML Interleukin-18 produced by peripheral blood cells is increased in Alzheimer's disease and correlates with cognitive impairmentBrain Behav Immun2008 22487492
Not in our library10.1016/j.bbi.2007.10.001
112.
Di Rosa M Dell'Ombra N Zambito AM Malaguarnera M Nicoletti F Malaguarnera L Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementiaEur J Neurosci2006 2326482656
Not in our library10.1111/j.1460-9568.2006.04780.x
113.
Yu JT Tan L Song JH Sun YP Chen W Miao D Tian Y Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer's diseaseBrain Res2009 1253169175
Not in our library10.1016/j.brainres.2008.11.083
114.
Bossu P Ciaramella A Moro ML Bellincampi L Bernardini S Federici G Trequattrini A Macciardi F Spoletini I Di Iulio F Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's diseaseJ Neurol Neurosurg Psychiatry2007 78807811
Not in our library10.1136/jnnp.2006.103242
115.
Segat L Milanese M Arosio B Vergani C Crovella S Lack of association between Interleukin-18 gene promoter polymorphisms and onset of Alzheimer's diseaseNeurobiol Aging2008 31162164
Not in our library10.1016/j.neurobiolaging.2008.03.005
116.
Iannello A Samarani S Debbeche O Tremblay C Toma E Boulassel MR Routy JP Ahmad A Role of interleukin-18 in the development and pathogenesis of AIDSAIDS Rev2009 11115125
Not in our library
117.
Sugama S Wirz SA Barr AM Conti B Bartfai T Shibasaki T Interleukin-18 null mice show diminished microglial activation and reduced dopaminergic neuron loss following acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatmentNeuroscience2004 128451458
Not in our library10.1016/j.neuroscience.2004.07.020
118.
Corcos M Guilbaud O Hjalmarsson L Chambry J Jeammet P Cytokines and depression: an analogic approachBiomed Pharmacother2002 56105110
Not in our library10.1016/s0753-3322(01)00156-1
119.
Dinan TG Inflammatory markers in depressionCurr Opin Psychiatry2009 223236
Not in our library10.1097/yco.0b013e328315a561
120.
Ganguli R Yang Z Shurin G Chengappa KN Brar JS Gubbi AV Rabin BS Serum interleukin-6 concentration in schizophrenia: elevation associated with duration of illnessPsychiatry Res1994 51110
Not in our library10.1016/0165-1781(94)90042-6
121.
Licinio J Wong ML The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotectionMol Psychiatry1999 4317327
Not in our library10.1038/sj.mp.4000586
122.
Myint AM Kim YK Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depressionMed Hypotheses2003 61519525
Not in our library10.1016/s0306-9877(03)00207-x
123.
Inflammation-related genes up-regulated in schizophrenia brains · 2007
No notice
124.
Appels A Bar FW Bar J Bruggeman C de Baets M Inflammation, depressive symptomtology, and coronary artery diseasePsychosom Med2000 62601605
Not in our library10.1097/00006842-200009000-00001
125.
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Not in our library10.1080/13550280490523706

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