Role Of IL-33 Research Articles

Clinical significance and intervention study of serum interleukin 18 in preeclampsia patients with coexisting obstructive sleep apnea

To investigate the role of IL-18 in the obstructive sleep apnea syndrome (OSAS)-induced preeclampsia (PE), by comparison of the changes of serum IL-18 levels among different groups as well as before and after continuous positive airway pressure (CPAP) treatment in pregnant women with both OSAS and PE. In control group there were 18 normal pregnant women with apnea hypopnea index (AHI) < 5. In simple PE group 18 pregnant PE patients with an AHI < 5 were recruited. In PE plus OSAS group 16 PE patients with coexisting OSAS were collected. CPAP treatment was performed for 1 week in 6 patients with AHI > 15 from PE plus OSAS group.Serum IL-18 levels were measured with ELISA. There was a significant difference in serum IL-18 levels among control group [(261 ± 95) ng/L], simple PE group [(382 ± 121) ng/L], and PE plus OSAS group [(601 ± 89) ng/L, all P < 0.001]. Following CPAP treatment, there was a significant decrease in AHI, systolic blood pressures, and serum IL-18 levels, but a significant increase in minimal SpO₂ (P < 0.01). Our study demonstrated that serum IL-18 levels in PE patients with OSAS were significantly elevated, which suggested that OSAS might increase the incidence of PE by enhancing inflammatory response, while CPAP treatment could effectively improve the pathological process.

Altered serum levels of IL-33 in patients with advanced systolic chronic heart failure: correlation with oxidative stress

BackgroundInterleukin-33 (IL-33) has been linked to chronic heart failure (CHF) in animal studies, but data on serum IL-33 levels in human CHF are not available. We analyzed levels of IL-33 in serum, and investigated the possible role of IL-33 in oxidative stress.MethodsA total of 191 subjects with advanced systolic CHF (CHF group), 175 patients with pre-existing cardiac diseases but no CHF (non-CHF group), and 177 healthy controls (HC group) were enrolled. Serum levels of IL-33, soluble ST2 (sST2) and N-terminal-pro-brain natriuretic peptide (NT-proBNP), malondialdehyde (MDA) content, erythrocyte superoxide dismutase (eSOD) activity, as well as left ventricular ejection fraction (LVEF), were determined. The exact form of IL-33 in serum was identified. Effects of IL-33 and sST2 on MDA content and SOD activity in angiotensin (Ang II)-stimulated AC16 cells were assessed.ResultsSerum levels of IL-33 and sST2 were elevated in CHF patients, whereas IL-33/sST2 ratios were decreased. In CHF patients, pre-existing cardiac diseases and medications used upon hospital admission did not affect IL-33 concentrations or the IL-33/sST2 ratio. Full-length IL-33, which could not be detected in serum from HC and barely detected in non-CHF patients, was significantly up-regulated in CHF patients. IL-33 levels were positively correlated with markers of CHF severity. IL-33/sST2 ratios were slightly and negatively related to MDA concentrations. IL-33 directly reduced MDA and enhanced SOD activity in Ang II-stimulated AC16 cells, which were greatly attenuated by sST2.ConclusionsSerum levels of IL-33, especially the full-length form, were elevated in CHF patients whereas IL-33 bioactivity was reduced. In advanced CHF, IL-33 may exert anti-oxidation effects, which may be overwhelmed by concurrently elevated levels of sST2.

Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.

6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.

The role of interleukin (IL)-22 on the proliferation of human keratinocyte cell line, HaCaT by Ultraviolet B (UVB) irradiation (44.27)

Abstract Interleukin 22 (IL-22), a member of IL-10 family, is a potent mediator of inflammatory responses. It is produced by activated CD4+ T cells and natural killer (NK) cells, but its receptor expression is restricted to nonhematopoietic cells in the skin, pancreas, intestine, liver, lung and kidney. IL-22 suppresses IL-4 production from Th2 cells and induces acute phase proteins in liver and pancreas. It is recently found that IL-22 plays a critical role in the maintenance of epidermal homeostasis by controlling cell cycle of keratinocytes. Therefore, we investigated that role of IL-22 on the proliferation of UVB-irradiated human keratinocytes, HaCaT. First, we found the increase of IL-22 mRNA expression was increased in HaCaT by UVB irradiation (150J/m2). When UVB-irradiated HaCaT was cultured in the presence of recombinant IL-22, the suppressed proliferation of HaCaT by UVB was rescued. It was closely related with the progression of cell cycle in UVB-irradiated HaCaT. We confirmed that the hyperproliferation and cell cycle progression of UVB-irradiated HaCaT by the addition of activated T cells or its culture supernatant. Taken together, IL-22 plays a critical role in the deterioration of epidermal hyperplasia by UVB irradiation. And it suggests that UVB-induced skin inflammation could effectively be controlled by the regulation of IL-22 production and its action on keratinocytes.

HCV and HIV stimulate production of the inflammatory cytokine IL-18 through activation of the Nalp3 inflammasome in monocytes (108.12)

Abstract Activation of the inflammasome-complex leads to production of the pro-inflammatory, inflammasome-associated cytokines IL-18 and IL-1β. These cytokines amplify the innate antiviral immune response and skew the developing adaptive immune response. We previously reported that IL-18 is the earliest host response to hepatitis C virus (HCV) infection and remains elevated at low levels in chronic infection. Our group has also reported an association between IL-18 SNPs and likelihood of HCV clearance. Despite these observations, the role of IL-18 in control of viruses capable of chronic infection is unknown. We now show that IL-18 is also elevated in persons with uncontrolled HIV and to a lesser extent in those with natural immunologic control of the virus. To understand inflammasome activity during chronic viral infection, we studied the interaction of HCV or HIV infected plasma and PBMC subsets from HIV and HCV uninfected subjects. We determined that (1) monocytes cultured with plasma from HIV or HCV viremic individuals produce IL-18 and other pro-inflammatory cytokines; (2) the virion is the inflammasome stimulating component within plasma, (3) siRNA knockdown of Nalp3 in monocytes modulates HCV and HIV induction of IL-18. Our data elucidate mechanisms by which HCV and HIV activate the inflammasome complex and demonstrate the production of inflammatory cytokines through the interaction of HIV and HCV and monocytes.

IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation (59.8)

Abstract BACKGROUND: IL-22 functions as both a proinflammatory and an anti-inflammatory cytokine in various inflammations. However, the roles of IL-22 in the allergic airway inflammation are still largely unknown. OBJECTIVE: We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. METHODS: We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). RESULTS: Antigen inhalation induced IL-22 production in CD4(+) T cells. Only one third of IL-22-producing CD4(+) T cells also produced IL-17A. Anti-IL-22 antibody administration enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of rIL-22 attenuated eosinophil recruitment. Moreover, anti-IL-22 antibody enhanced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1β- or LPS-stimulated MLE-15 cells. CONCLUSION: IL-22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells.

Role of IL-22 in protecting mucosal barrier disruption by HIV-1

Role of IL-22 in protecting mucosal barrier disruption by HIV-1

Tu1860 Inverse Expression of IL-33 in TH1 Versus TH2 Mediated Experimental Colitis

Background: Interleukin (IL)-33 is a pro-inflammatory cytokine that has been associated with induction of human T helper 2 (TH2)-type inflammatory responses through activation of the ST2 receptor. Recent research has shown that IL-33 is upregulated in active ulcerative colitis (UC), but the role of IL-33 in regulation of intestinal mucosal immunologic reactions is uncertain. Aim: The aim of the present study was to describe the regulation of IL-33 in a TH1 and a TH2 model of experimental colitis, to determine if IL-33 is also regulated according to the T helper cell profile in the inflamed intestinal mucosa. Methods: Expression of IL-33 was investigated in dextran sodium sulphate (DSS)-induced colitis (a TH2-type of inflammation) and in the T-cell transfer model of colitis (SCID colitis) (a TH1-type of inflammation). The colonic IL-33 mRNA expression was analyzed by a quantitative realtime polymerase chain reaction (qRT-PCR). IL-33 protein expression and its localization were investigated by immunoblotting and by standard immunohistochemical procedures. The association between IL-33 expression and clinical outcome measures including the disease activity index (DAI), colon length, and histological inflammation scores was determined. Results: The colonic IL-33 mRNA expression was significantly up-regulated in the experimental DSS colitis model (p<0.05), and significantly down-regulated in the SCID colitis (p<0.01). Our results showed an increased number of IL-33 positive cells in DSS colitis localized to lamina propria inflammatory cells, whereas IL-33 protein expression in SCID colitis was abolished. IL-33 expression correlated positively with the DAI-score (p<0.001), colon length (p<0.001), and the histological inflammation score (p<0.001) of the DSS model. Conclusions: The present study demonstrates that colonic IL-33 expression in mice is highly dependent on the type of mucosal inflammatory response induced, being high in TH2-type inflammatory conditions, and low in TH1-type inflammatory responses. IL-33 might be a key determinant of the nature of the colonic mucosal inflammation and thus be of importance for the development of inflammatory bowel disease. Inhibition of IL33 signalling could in this way be a potential therapeutic target in UC which is driven by a TH2-type inflammatory reaction.

Tu1861 The IBD Associated Gene, Protein Tyrosine Phosphate Non Receptor Type 22, Modulates Interferon-γ Induced Cytokine Responses in Human Monocytes

Background: Interleukin (IL)-33 is a pro-inflammatory cytokine that has been associated with induction of human T helper 2 (TH2)-type inflammatory responses through activation of the ST2 receptor. Recent research has shown that IL-33 is upregulated in active ulcerative colitis (UC), but the role of IL-33 in regulation of intestinal mucosal immunologic reactions is uncertain. Aim: The aim of the present study was to describe the regulation of IL-33 in a TH1 and a TH2 model of experimental colitis, to determine if IL-33 is also regulated according to the T helper cell profile in the inflamed intestinal mucosa. Methods: Expression of IL-33 was investigated in dextran sodium sulphate (DSS)-induced colitis (a TH2-type of inflammation) and in the T-cell transfer model of colitis (SCID colitis) (a TH1-type of inflammation). The colonic IL-33 mRNA expression was analyzed by a quantitative realtime polymerase chain reaction (qRT-PCR). IL-33 protein expression and its localization were investigated by immunoblotting and by standard immunohistochemical procedures. The association between IL-33 expression and clinical outcome measures including the disease activity index (DAI), colon length, and histological inflammation scores was determined. Results: The colonic IL-33 mRNA expression was significantly up-regulated in the experimental DSS colitis model (p<0.05), and significantly down-regulated in the SCID colitis (p<0.01). Our results showed an increased number of IL-33 positive cells in DSS colitis localized to lamina propria inflammatory cells, whereas IL-33 protein expression in SCID colitis was abolished. IL-33 expression correlated positively with the DAI-score (p<0.001), colon length (p<0.001), and the histological inflammation score (p<0.001) of the DSS model. Conclusions: The present study demonstrates that colonic IL-33 expression in mice is highly dependent on the type of mucosal inflammatory response induced, being high in TH2-type inflammatory conditions, and low in TH1-type inflammatory responses. IL-33 might be a key determinant of the nature of the colonic mucosal inflammation and thus be of importance for the development of inflammatory bowel disease. Inhibition of IL33 signalling could in this way be a potential therapeutic target in UC which is driven by a TH2-type inflammatory reaction.

The role of IL-18 in atopic dermatitis

Evaluation of: Kou K, Aihara M, Matsunaga T et al. Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis. Arch. Dermatol. Res. doi:10.1007/s00403-011-1198-9 (2011) (Epub ahead of print).Atopic dermatitis (AD) is a frequent, chronic, inflammatory skin disease. Immunological and genetic factors followed by skin barrier dysfunction are the main causes of AD development. IL-18 is considered as a new factor involved in AD pathogenesis. The previous studies confirmed that the serum level of IL-18 is elevated in patients with AD, but its association with severity of the disease remains ambiguous. We review the recent paper by Kou et al. that identified biomarkers associated with clinical severity in adult AD patients. Results from this study indicate that IL-18 levels are significantly associated with Scoring Atopic Dermatitis (SCORAD) score, as well as TARC, total IgE and LDH levels. The authors suggest that a panel of these biomarkers may be a more usef...

Roles for IL-33 and TSLP in Chronic Eosinophilic Airway Inflammation Induced by Airborne Allergen Exposure

A majority of experimental mouse models of asthma reflect acute airway inflammation induced by specific antigen [e.g. ovalbumin (OVA)] in sensitized animals. Because chronic airway inflammation is a distinct feature of human asthma, we sought to develop a mouse model to mimic the pathology and elucidate the immunological mechanisms.

P002 The potential role of IL-33 in inflammatory-associated gut fibrosis: Induction of pro-fibrogenic gene expression and myofibroblast hypertrophy

Background: The pathogenesis of human ulcerative colitis (UC) is characterized by the presence of IL-13-producing Natural Killer T cells (NKT cells). One major complication of UC is the development of colitis-associated colorectal cancer. In these studies we determined the role of alternatively activated “M2 macrophages” in a new mouse model of colitis-associated carcinogenesis. Further, we verified these results through immunological analysis of surgical specimens obtained from patients with UC-associated colon cancer. Methods: Studies were performed using a mouse model for colitis-associated carcinogenesis based on chronic Oxazolonecolitis in combination with an initial i.p. azoxymethane (AOM) injection in female BALB/c mice. We observed chronic intestinal inflammation lasting for 12 weeks in mice repeatedly administered Oxazolone. Surgical specimens with UC-associated colon cancer were analyzed by flow cytometry and immunohistochemistry. Results: We could show that Oxazolone-colitis was mediated by colonic alpha-galactosyl-ceramide+CD1+ NKT-cells producing IL-13 and therefore resembles the immunological characteristics of human UC. Colon cancer development in this model was dependent on F4/80+CD11bhighGr1low macrophages producing IL-6 and EGF. Those cells inherited phenotypic characteristics of IL-13-stimulated alternativelyactivated “M2 macrophages”. To elucidate the importance of these “M2 macrophages”, we conducted bone marrow chimera studies and demonstrated that innate immune signaling through MyD88 in “M2 macrophages” is the key event for the production of tumor supporting factors like IL-6 and EGF. In surgical specimens obtained from patients with UC-associated colon cancer we verified those experimental findings. We consistently found a dense accumulation of IL-13-producing NKT cells inside the tumors. In addition, in this IL-13-dominated tumor micromilieu CD14+ and CD68+ antigen-presenting cells accumulated intensively and those antigen-presenting cells demonstrated an alternatively activated “M2 phenotype” by the expression of CD163 and CD205. Conclusions: We could demonstrate that in an experimental UC model, as well as in human UC, pathogenic IL-13producing NKT cells accumulate in the tumor micromilieu of UC-associated colon cancers. This immunologic situation inside the tumor microenvironment of mice and men induces tumor promoting M2 macrophages. Therefore M2 macrophages represent a potential target for future therapeutic strategies.

40 Contribution of IL-33 and Nuocyte to Experimental Allergic Dermatitis

BackgroundIL-33 is a member of the IL-1 family cytokines and the ligand of ST2 (IL-33R alpha chain). IL-33 stimulates Th2 cells, basophils, mast cells, and nuocyte, a recently discovered new lymphocyte, to produce various cytokines. We have previously shown that the serum level of IL-33 is significantly elevated in patients with Japanese cedar pollinosis1 and IL-33 has the potential to induce Th2 cytokine-mediated allergic conjunctivitis2. As these results suggest that IL-33 may also have some relations to allergic dermatitis, we now examined the pathological role of IL-33 in dermatitis. First, we investigated an immediate reaction of skin by challenging BALB/c mice with DNFB repeatedly. We also tested the involvement of natural helper cells (nuocyte) in dermatitis of NC/Nga mice.Methods(1) Wild-type BALB/c mice or ST2 KO mice were sensitized and repeatedly challenged with DNFB on the left ear at 1 week intervals. When they are challenged 4 or 5 times, the ear shows biphasic (bimodal) responses which consist of an immediate phase and a delayed-type reaction. (2) When NC/Nga mice are raised in conventional (non-SPF) circumstances, skin lesions that are clinically similar to human atopic dermatitis spontaneously appears on the skin. We separated lymphocytes from the inflamed skin of NC/Nga mice using collagenase I (Sigma-Aldrich) and counted the numbers of nuocytes (ST2+/Sca-1+/lineage marker-negative) by FACS.Results(1) The reactions were hapten specific. Wild-type BALB/c mice showed both immediate and delayed-type reactions, whereas ST2 KO mice did not show any immediate reaction. (2) When IL-33 was administered subcutaneously, NC/Nga mice showed increase of serum IgE level. The number of nuocytes in inflamed skin of NC/Nga mice significantly increased compared to non-inflamed skin. The nuocytes showed very weak expression of ST2 in non-inflamed skin, whereas the expression of ST2 in inflamed skin was very significant.ConclusionsThese results suggest that IL-33 may have an important role in the mechanism of immediate contact hypersensitivity, and nuocytes may contribute to the development of atopic dermatitis-like skin lesion in NC/Nga mice.

Association of IL-18 genotype with impaired glucose regulation in Korean women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age. The pro-inflammatory cytokine, interleukin (IL)-18, is associated with metabolic syndrome, and elevated serum IL-18 levels are related to obesity and insulin resistance in PCOS patients. However, the role of IL-18 in the PCOS remains unclear. So we examined whether or not two functional polymorphisms in the IL-18 gene, -137G>C and +183A>G, are associated with PCOS itself or glucose intolerance in Korean women with PCOS. The IL-18 genotypes of 126 women with PCOS and 113 controls were determined and their serum levels of lipid and hormone profiles measured. The insulin resistance index was calculated from the glucose and insulin concentrations obtained by oral glucose tolerance tests. There were no statistically significant differences in the distribution of -137 G>C polymorphisms among the women classified according to presence or absence of PCOS and obesity. However, the -137G/G allele was more frequent in the PCOS+impaired glucose regulation (IGR) group than PCOS+normal glucose tolerance group (X(2)=7.637, p(Bonf)=0.022). The PCOS group with only the -137G allele had a significantly increased risk of IGR compared to the PCOS group with the -137C allele (92 vs. 8%, odds ratio=6.325, 95% confidence interval=1.403-28.519). In the PCOS patients, the mean fasting and 2-h post-prandial plasma glucose level of patients with only the -137G allele was significantly higher than those of the patients with the -137C allele (88.87 ± 9.49 vs. 84.37 ± 6.19, p=0.002 and 120.07 ± 34.53 vs. 107.54 ± 27.13, p=0.038). Only one woman was heterozygous for the +183A>G polymorphism and the other 224 subjects were homozygous for the polymorphism (A/A). The IL-18 -137G allele could play a role in the predisposition to glucose intolerance in Korean women with PCOS, and the +183G allele of IL-18 is not associated with the Korean population.

The role of IL-22 in the pathogenesis of skin diseases

IL-22 is an IL-10 family cytokine that acts mainly on epithelial cells. It is produced by immune cell subsets, including CD4⁺ T cells, natural killer cells, and natural killer T cells. In the skin, IL-22 mediates keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and induces the production of antimicrobial proteins. Although IL-22 production was initially linked with IL-17 expression in Th17 cells, IL-22 production can also occur in an apparently unique subset of cells that lacks the production of IL-17 and IFN-γ (Th22). Interestingly, Th22 cells express skin homing chemokine receptors CCR4 and CCR10. Indeed, Th22 cells reside in the normal skin and are shown to be enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases. Although psoriasis is the first example of an organ-specific immune disorder for which the role of IL-22 has been comprehensively studied, a growing body of evidence indicates that this cytokine also plays a critical role in the pathogenesis of atopic dermatitis. In this review, we discuss the role of IL-22 in the pathogenesis of skin diseases, particularly focusing on psoriasis and atopic dermatitis. Targeting IL-22 may have promise as a potential therapeutic for various skin diseases.

撤回： IL-33とアレルギー性炎症

撤回： IL-33とアレルギー性炎症

Role of IL-33 and Eosinophils in Intestinal Inflammation

IL-33, a recently identified cytokine, is linked to autoimmune and inflammatory diseases. Several studies define increased expression of IL-33 in the affected mucosa of patients with inflammatory bowel diseases (IBD). IL-33 can induce Th2 cytokine production and leukocyte mediator release. While eosinophils have been circumstantially associated with inflammatory bowel diseases (IBDs), very recent studies suggest IL-33 impacts eosinophil's function by increasing eosinophil adhesiveness to extracellular matrix and inducing inflammatory mediator release in IBD. The goal of this project is to identify mechanisms by which IL-33 impacts eosinophil function during intestinal inflammation in murine models of IBD. We hypothesize that IL-33 increases eosinophil degranulation and intestinal inflammation. Primary peripheral human blood eosinophils were isolated and assessed immediately or were cultured for 3 hours in the presence of IL-33 or other cytokines including IL-5, IL-1β, TNF-α or IFN-γ for flow cytometric assessment of the IL-33 cognate receptor ST2. Eosinophils were also assessed for the release of the eosinophil granule protein eosinophil peroxidase (EPO) and electron microscopic techniques. Alterations in cytokine expression were analyzed by real time RT-PCR. The impact of IL-33 on eosinophil migration was measured using an in vitro colonic epithelial (T84 cell) transwell-migration assay. In vivo analysis of IL-33 and eosinophils in mouse models of inflammatory bowel disease (IBD) employed the DSS colitis model in addition to the SAMP1/SkuSlc model of Th2 cytokine associated eosinophilic ileitis. Human tissue from IBD patients were assessed for eosinophilic inflammation and IL-33 by immunohistochemistry. The membrane bound IL-33 receptor, ST2, was present on freshly isolated human peripheral blood eosinophils. This level was further increased following incubation with IL-33 (100ng/ml) and IL-5 as well as the IBD associated IL-1β, TNF-α or IFN-γ cytokines (all 100ng/ml). IL-33 induced eosinophil degranulation as recorded by biochemical assay (>4-fold, p<0.05). In addition electron microscopic evidence demonstrated IL-33 induced eosinophil granule depletion. Stimulation of eosinophils with IL-33 led to production of IL-8 (>6-fold, p<0.01) and IL-13 (∽20-fold, p<0.001) compared to unstimulated cells. IL-33 induced increased eosinophil migration into the colonic epithelium (>3-fold). DSS colitis induced a robust increase in colonic eosinophils, ST2 transcript (>15-fold, p<0.01) as well as IL-33 mRNA (epithelial ∽30-fold, p<0.05 and whole tissue >6-fold, p<0.001). Similar findings were detected in another model of ileal involved IBD, SAMP1/SkuSlc mice. Following treatment of SAMP1/SkuSlc mice with anti-CCR3 antibody a significant decrease in ileal eosinophils (0.5-fold, p<0.001) and IL-33 was observed (0.25-fold, p<0.001). Eosinophilic inflammation and the cytokine IL-33 was increased in human IBD tissue specimens. Eosinophil activation by the pro-inflammatory cytokine IL-33 may contribute to eosinophil activation and intestinal inflammation.

A subset of dendritic cells as a major and constitutive source of IL-22BP

IL-22 is a cytokine produced by T cells and innate lymphocytes. Its receptor is exclusively expressed by non hematopoietic cells mostly epithelial cells and hepatocytes. IL-22 has pathogenic or protective effects depending on the model. A role for IL-22 is suggested in IMID such as psoriasis, rheumatoid arthritis and Crohn disease. IL-22BP is a soluble inhibitory receptor specific for IL-22 whose cellular source and physiological role are mainly unknown.

Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus

We have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility to Aspergillus fumigatus lung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense against A. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early after A. fumigatus challenge. Culturing cells from enzymatic lung digests ex vivo further demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1β, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice. In vivo neutralization of IL-22 in the lungs of WT mice resulted in impaired A. fumigatus lung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden after A. fumigatus challenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1β production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from both A. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity against A. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impaired A. fumigatus clearance. Moreover, lung S100a8, S100a9, and Reg3g mRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1-dependent IL-22 production.

IL‐33 synergizes with TCR and IL‐12 signaling to promote the effector function of CD8+ T cells

The effector functions of CD8(+) T cells are influenced by tissue inflammatory microenvironments. IL-33, a member of the IL-1 family, acts as a danger signal after its release during cell necrosis. The IL-33/ST2 axis has been implicated in various Th2 responses. Its role in CD8(+) T-cell-mediated immune response is, however, not known. Here we find that type 1 cytotoxic T (Tc1) cells cultured in vitro unexpectedly express high levels of the IL-33 receptor ST2. Interestingly, the expression of ST2 in Tc1 cells is dependent on T-bet, a master Th1/Tc1 transcription factor. In addition, IL-33 enhances TCR-triggered IFN-γ production. IL-33 together with IL-12 can stimulate IFN-γ production in Tc1 cells. Moreover, IL-33 synergizes with IL-12 to promote CD8(+) T-cell effector function. The synergistic effect of IL-33 and IL-12 is partly mediated by Gadd45b. Together, these in vitro data establish a novel role of IL-33 in promoting effector type 1 adaptive immune responses.