Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells.

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8+ T cells and endogenous CD8+ T cells. Endogenous CD8+ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR-MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells.

In Situ Maturation and Tissue Adaptation of Type 2 Innate Lymphoid Cell Progenitors.

Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.

IL-18R signaling is required for γδ T cell response and confers resistance to Trypanosoma cruzi infection.

IFN-γ-producing γδ T cells have been suggested to play an important role in protection against infection with Trypanosoma cruzi. However, little is known about the mechanisms leading to functional differentiation of this T cell subset in this model. In the current work, we investigated the possibility that the IL-18/MyD88 pathway is central for the generation of effector γδ T cells, playing a role for resistance against infection. We found that splenic γδ+ CD3+ cells were rapidly expanded (10-14 days post infection), which was accompanied by an early γδ T cell infiltration into the heart. In the following days, intracardiac parasitism was reduced, the protective immunity being accompanied by decreased γδ T cells tissue infiltration. As predicted, there was a drastic reduction of γδ T cells in Myd88- and Il18r1-deficient mice, both transgenic strains displaying a susceptible phenotype with increased intracardiac parasitism. In vivo and in vitro assays confirmed that IL-18R deficiency hampered γδ T cell proliferation. Further characterization revealed that T. cruzi infection up-regulates IL-18R expression in WT γδ+ T cell population whereas Il18r1-/- mice showed impaired generation of cytotoxic GzB+ and IFN-γ-producing γδ T cells. Consistently, in vitro cytotoxicity assay confirmed that cytolytic function was impaired in Il18r1-deficient γδ T cells. As a proof of concept, adoptive transfer of WT γδ T cells rescues Il18r1-deficient mice from susceptibility, reducing parasitemia and abrogating the mortality. Collectively, our findings implicate the IL-18R-MyD88 signaling in the mechanisms underlying generation of immunoprotective γδ T cells response in experimental Trypanosoma cruzi infection.

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis.

Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.

Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failure.

Interleukin-18 (IL-18), also known as interferon-gamma (IFN-γ)-inducing factor, is involved in Th1 responses and regulation of immunity. Accumulating evidence implicates IL-18 in autoimmune diseases, but little is known of its role in acquired aplastic anemia (AA), the immune-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). IL-18 protein levels were significantly elevated in sera of severe AA (SAA) patients, including both responders and nonresponders assayed before treatment, and decreased after treatment. IL-18 receptor (IL-18R) was expressed on HSPCs. Co-culture of human BM CD34+ cells from healthy donors with IL-18 upregulated genes in the helper T-cell and Notch signaling pathways and downregulated genes in the cell cycle regulation, telomerase, and IL-6 signaling pathways. Plasma IL-18 levels were also elevated in murine models of immune-mediated BM failure. However, deletion of IL-18 in donor lymph node cells or deletions of either IL-18 or IL-18R in recipients did not attenuate elevations of circulating IFN-γ, tumor necrosis factor-alpha, or IL-6, nor did they alleviate BM failure. In summary, our findings suggest that, although increased circulating IL-18 is a feature of SAA, it may reflect an aberrant immune response but be dispensable to the pathogenesis of AA.

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability.

BACKGROUND/AIMS: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. METHODS: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. RESULTS: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. CONCLUSION: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

Mast cell in innate immunity mediated by proinflammatory and antiinflammatory IL-1 family members.

Innate immunity consists of physical and chemical barriers which provide the early defense against infections. Innate immunity orchestrates the defense of the host with cellular and biochemical proteins. Mast cells (MCs) are involved in innate and adaptive immunity and are the first line of defense which generates multiple inflammatory cytokines/chemokines in response to numerous antigens. MC-activated antigen receptor Fc-RI provokes a number of important biochemical pathways with secretion of numerous vasoactive, chemoattractant and inflammatory compounds which participate in allergic and inflammatory diseases. MCs can also be activated by Th1 cytokines and generate pre-formed and de novo inflammatory mediators, including TNF. IL-37 is an anti-inflammatory cytokine which binds IL-18R-alpha chain and reduces the production of inflammatory IL-1 family members. IL-37 down-regulates innate immunity by inhibiting macrophage response and its accumulation and reduces the cytokines that mediate inflammatory diseases. Here, we discuss the relationship between MCs, innate immunity, and pro-inflammatory and anti-inflammatory cytokines.

IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants.

Designing modern vaccine adjuvants depends on understanding the cellular and molecular events that connect innate and adaptive immune responses. The synthetic TLR4 agonist glycopyranosyl lipid adjuvant (GLA) formulated in a squalene-in-water emulsion (GLA-SE) augments both cellular and humoral immune responses to vaccine Ags. This adjuvant is currently included in several vaccines undergoing clinical evaluation including those for tuberculosis, leishmaniasis, and influenza. Delineation of the mechanisms of adjuvant activity will enable more informative evaluation of clinical trials. Early after injection, GLA-SE induces substantially more Ag-specific B cells, higher serum Ab titers, and greater numbers of T follicular helper (TFH) and Th1 cells than alum, the SE alone, or GLA without SE. GLA-SE augments Ag-specific B cell differentiation into germinal center and memory precursor B cells as well as preplasmablasts that rapidly secrete Abs. CD169+ SIGNR1+ subcapsular medullary macrophages are the primary cells to take up GLA-SE after immunization and are critical for the innate immune responses, including rapid IL-18 production, induced by GLA-SE. Depletion of subcapsular macrophages (SCMф) or abrogation of IL-18 signaling dramatically impairs the Ag-specific B cell and Ab responses augmented by GLA-SE. Depletion of SCMф also drastically reduces the Th1 but not the TFH response. Thus the GLA-SE adjuvant operates through interaction with IL-18-producing SCMф for the rapid induction of B cell expansion and differentiation, Ab secretion, and Th1 responses, whereas augmentation of TFH numbers by GLA-SE is independent of SCMф.

Exome analysis of patients with concurrent pediatric inflammatory bowel disease and autoimmune disease.

BACKGROUND: Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. METHODS: Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. RESULTS: Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P < 0.05) before Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1, and IL18R1) and 3 in asthma only (PYHIN1, IL2RB, and GSTP1). CONCLUSIONS: One-third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients.

IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction.

Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.

Type I IFNs and IL-18 regulate the antiviral response of primary human γδ T cells against dendritic cells infected with Dengue virus.

Little is known about the cellular mechanisms of innate immunity against dengue virus (DV) infection. Specifically, the γδ T cell response to DV has not been characterized in detail. In this article, we demonstrate that markers of activation, proliferation, and degranulation are upregulated on γδ T cells in PBMC isolated from individuals with acute dengue fever. Primary γδ T cells responded rapidly in vitro to autologous DV-infected dendritic cells by secreting IFN-γ and upregulating CD107a. The anti-DV IFN-γ response is regulated by type I IFN and IL-18 in a TCR-independent manner, and IFN-γ secreting γδ T cells predominantly expressed IL-18Rα. Antagonizing the ATP-dependent P2X7 receptor pathway of inflammasome activation significantly inhibited the anti-DV IFN-γ response of γδ T cells. Overnight priming with IL-18 produced effector γδ T cells with significantly increased ability to lyse autologous DV-infected dendritic cells. Monocytes were identified as accessory cells that augmented the anti-DV IFN-γ response of γδ T cells. Lack of monocytes in culture is associated with lower IL-18 levels in culture supernatant and diminished production of IFN-γ by γδ T cells, whereas addition of exogenous IL-18 restored the IFN-γ response of γδ T cells in monocyte-depleted cocultures with DV-infected DC. Our results indicate that primary γδ T cells contribute to the immune response during DV infection by providing an early source of IFN-γ, as well as by killing DV-infected cells, and suggest that monocytes participate as accessory cells that sense DV infection and amplify the cellular immune response against this virus in an IL-18-dependent manner.

Involvement of interleukin-18 in the pathogenesis of human eosinophilic esophagitis.

IL-18 is induced in food allergy and EoE is food allergen-induced disease. Therefore, we tested the hypothesis whether IL-18 is involved in food allergen-induced EoE pathogenesis. Accordingly, we examined normal SPT+ and SPT- EoE patient blood and biopsy samples for IL-18, IL-18Rα, ICAM and VCAM expression. Herein, we show increased IL-18 level is highly significant in food allergen SPT+ compared to SPT- EoE patients. We also report that IL-18Rα+ cells and mRNA levels are induced in the esophageal biopsies of EoE patients and blood IL-18 levels correlate with esophageal eosinophilia (P<0.01). Additionally, we report that the levels of esophageal eosinophil and mast cells correlate with ICAM expression in human EoE. Mechanistically, we show that IL-18 in vitro stimulates iNKT cells and endothelial cells and induce eosinophil active cytokines IL-5 and IL-13. We provide the evidence that IL-18 is critical cytokine involved in activation of iNKT cells and ICAM in promoting human EoE.

The IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1 expression and signaling through innate receptor-initiated pathways.

Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in pattern-recognition receptor (PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel disease. Multiple gene loci are associated with inflammatory bowel disease, but their functional effects are largely unknown. One such region in chromosome 2q12 (rs917997), also associated with other immune-mediated diseases, encompasses IL18RAP. We found that human monocyte-derived macrophages (MDMs) from rs917997 AA risk carriers secrete significantly less cytokines than G carriers upon stimulation of multiple PRRs, including nucleotide-binding oligomerization domain 2 (NOD2). We identified that IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced cytokine secretion in MDMs. IL-18RAP responded to NOD2-initiated early, caspase-1-dependent autocrine IL-18, which dramatically enhanced MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation was sufficient to rescue decreased cytokines in NOD2-stimulated IL-18RAP-deficient MDMs. Relative to GG carriers, MDM from rs917997 AA carriers had decreased expression of cell-surface IL-18RAP protein, as well as of IL-18R1 and IL-1R1, genes also located in the IL18RAP region. Accordingly, these risk-carrier MDMs show diminished PRR-, IL-18-, and IL-1-induced MAPK and NF-κB signaling. Taken together, our results demonstrate clear functional consequences of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1, and IL-1R1 protein expression, which impairs autocrine IL-18 and IL-1 signaling, thereby leading to decreased cytokine secretion in MDMs upon stimulation of a broad range of PRRs.

Development of autoimmune hair loss disease alopecia areata is associated with cardiac dysfunction in C3H/HeJ mice.

Alopecia areata (AA) is a chronic autoimmune hair loss disease that affects several million men, women and children worldwide. Previous studies have suggested a link between autoimmunity, stress hormones, and increased cardiovascular disease risk. In the current study, histology, immunohistology, quantitative PCR (qPCR) and ELISAs were used to assess heart health in the C3H/HeJ mouse model for AA and heart tissue response to adrenocorticotropic hormone (ACTH) exposure. Mice with AA exhibited both atrial and ventricular hypertrophy, and increased collagen deposition compared to normal-haired littermates. QPCR revealed significant increases in Il18 (4.6-fold), IL18 receptor-1 (Il18r1; 2.8-fold) and IL18 binding protein (Il18bp; 5.2-fold) in AA hearts. Time course studies revealed a trend towards decreased Il18 in acute AA compared to controls while Il18r1, Il18bp and Casp1 showed similar trends to those of chronic AA affected mice. Immunohistochemistry showed localization of IL18 in chronic AA mouse atria. ELISA indicated cardiac troponin-I (cTnI) was elevated in the serum and significantly increased in AA heart tissue. Cultures of heart atria revealed differential gene expression between AA and control mice in response to ACTH. ACTH treatment induced significant increase in cTnI release into the culture medium in a dose-dependent manner for both AA and control mice. In conclusion, murine AA is associated with structural, biochemical, and gene expression changes consistent with cardiac hypertrophy in response to ACTH exposure.

Expression of IL-1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL-1F8 and IL-1F9.

We report for the first time that expression of the novel IL-1 cytokine receptor IL-1Rrp2 (IL-1R6) is unique to DCs within the human myelomonocytic lineage. IL-1Rrp2 was expressed by monocyte-derived dendritic cells (MDDCs) which was dose-dependently increased by IL-4 and correlated with increased numbers of differentiated MDDCs. Human plasmacytoid DCs also express IL-1Rrp2 but the receptor is not expressed by either myeloid DC type 1 (mDC1) or mDC2 cells. We also show that IL-1F8 or IL-1F9 cytokines, which signal through IL-1Rrp2, induce maturation of MDDCs, as measured by increased expression of HLA-DR and CD83 and decreased expression of CD1a. Furthermore, IL-1F8 stimulated increased CD40 and CD80 expression and IL-18 and IL-12 p70 production by MDDCs, which induced proliferation of IFN-γ-producing CD3(+) lymphocytes (indicative of inflammatory Th1 subsets). IL-1F8 and IL-1F2 were equipotent in their ability to stimulate IL-18 secretion from MDDCs but IL-1F8 was not as potent as IL-1F2 in stimulating secretion of IL-12p70 from MDDCs or inducing lymphocyte proliferation Therefore, IL-1Rrp2 expression by some DC subsets may have an important function in the human immune response in vivo via its role in differentiation of inflammatory Th1 lymphocytes.

Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections.

During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rα(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rα(hi) memory cells upregulated CD25 and produced IFN-γ, the IL-18Rα(lo) exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.

IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.

Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.

Mapping of the full length and the truncated interleukin-18 receptor alpha in the mouse brain.

The cytokine IL-18 acts on the CNS both in physiological and pathological conditions. Its action occurs through the heterodimeric receptor IL-18Ralpha\beta. To better understand IL-18 central effects, we investigated in the mouse brain the distribution of two IL-18Ralpha transcripts, a full length and an isoform lacking the intracellular domain hypothesized to be a decoy receptor. Both isoforms were expressed in neurons throughout the brain primarily with overlapping distribution but also with some unique pattern. These data suggest that IL-18 may modulate neuronal functions and that its action may be regulated through expression of a decoy receptor.

Recovery of IFN-gamma levels in PBMCs from lepromatous leprosy patients through the synergistic actions of the cytokines IL-12 and IL-18.

The shift to the production of a Th1 cytokine profile during an intracellular infection has been shown to depend on antigen presenting cells-derived IL-12 and T-cell-derived IFN-gamma production. IL-18 facilitates Th1 priming in synergy with IL-12 through the stimulation of IFN-gamma production by T cells, B cells, NK cells, macrophages and DCs. A low level of IFN-gamma production in PBMC cultures from lepromatous leprosy patients (LL) has been previously reported by several groups. We evaluated the synthesis of this cytokine after exogenous addition of recombinant IL-12 and IL-18 (IL12/IL18) in order to induce recovery of the IFN-gamma levels with Mycobacterium leprae antigenic stimulation. The aim of this study was to investigate if exogenous addition of IL12/IL18 to PBMC cell cultures in the presence of M. leprae antigens could induce recovery of IFN-gamma levels. We found that IFN-gamma levels in PBMCs cultured from LL patients were reestablished after exogenous addition of exogenous IL12/IL18 and we also observed a diminished IL-18R expression. Although the molecular mechanisms of IL12/IL18 synergy have not been clearly elucidated, we assume that recombinant cytokines can activate several transcription factors that induce IFN-gamma synthesis.

IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcepsilonRI signals.

The IL-1-related molecules, IL-1 and IL-18, can promote Th2 cytokine production by IgE/antigen-FcepsilonRI-stimulated mouse mast cells. Another IL-1-related molecule, IL-33, was identified recently as a ligand for T1/ST2. Although mouse mast cells constitutively express ST2, the effects of IL-33 on mast cell function are poorly understood. We found that IL-33, but not IL-1beta or IL-18, induced IL-13 and IL-6 production by mouse bone marrow-derived, cultured mast cells (BMCMCs) independently of IgE. In BMCMCs incubated with the potently cytokinergic SPE-7 IgE without specific antigen, IL-33, IL-1beta, and IL-18 each promoted IL-13 and IL-6 production, but the effects of IL-33 were more potent than those of IL-1beta or IL-18. IL-33 promoted cytokine production via a MyD88-dependent but Toll/IL-1R domain-containing adaptor-inducing IFN-beta-independent pathway. By contrast, IL-33 neither induced nor enhanced mast cell degranulation. At 200 ng/ml, IL-33 prolonged mast cell survival in the absence of IgE and impaired survival in the presence of SPE-7 IgE, whereas at 100 ng/ml, IL-33 had no effect on mast cell survival in the absence of IgE and reduced mast cell survival in the presence of IgE. These observations suggest potential roles for IL-33 in mast cell- and Th2 cytokine-associated immune responses and disorders.