IL-17 and Regulatory Cytokines (IL-10 and IL-27) in L. braziliensis Infection

Cutaneous leishmaniasis (CL) is characterized by high production of pro‐inflammatory cytokines and development of pathology. Individuals with subclinical L. braziliensis infection (SC) have a positive skin test to leishmania, but do not develop disease. We evaluated whether the downregulation of inflammatory response in SC is mediated by IL‐10 and IL‐27 and whether IL‐17 is associated with control of infection. Participants include SC individuals, patients with CL and healthy subjects. Cytokines protein and mRNA were detected by ELISA and real‐time PCR. IFN‐γ and TNF‐α levels were higher in CL than in SC group. The IL‐10 levels and mRNA for IL‐10 were similar in both SC and CL. mRNA for IL‐27 was increased in cells from SC after stimulation with L. braziliensis antigen. There was a tendency for increased levels of IL‐17 in SC compared to CL. The weak type 1 immune response observed in SC L. braziliensis infection is not because of the regulatory effects of IL‐10 and IL‐27. The control of Leishmania infection may be mediated by innate immune response with participation of IL‐17. The results from this pilot study warrant further larger studies to investigate the potential contributions of IL‐17 and IL‐27 to the control of L. braziliensis infection.     

Graves' disease and gene polymorphism of TNF-α, IL-2, IL-6, IL-12, and IFN-γ

The role of genetic factors in the pathogenesis of Graves' disease (GD) is not clear. The purpose of this study was to investigate the association between single nucleotide polymorphisms in pro-inflammatory cytokine genes and GD in Iranian patients. A case-control hospital-based study was carried out on 107 GD patients and 140 healthy controls. Cytokine typing was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP) assay. The allele and genotype frequencies of the following cytokine genes were determined: TNF-α (-308A/G, -238A/G), IL-2 (-330T/G, +166G/T), IL-6 (-174C/G, A/G nt565), IL-12 (-1188A/C), and IFN-γ (UTR 5644A/T). The following alleles and genotypes were significantly overrepresented in patients: TNF-α -308A allele (P < 0.01) and AA genotype (P < 0.05), IL-2 -330G allele (P < 0.01) and GG genotype (P < 0.01), IL-6 -174C allele (P < 0.01) and CC genotype (P < 0.01), IL-12 -1188C allele (P < 0.01) and CC genotype (P < 0.01), IFN-γ UTR5644T allele (P < 0.01) and TT genotype (P < 0.01). In conclusion, this is the first study to show a significant association between GD and IL-2 -330G, IL-12 -1188C, and IFN-γ UTR 5644T alleles. Our results support the hypothesis that polymorphism in pro-inflammatory cytokines might be involved in predisposition to GD.     

Serum TNF-α, IL-10 and IL-2 in Schizophrenic Patients Before and After Treatment with Risperidone and Clozapine

Background: Schizophrenia is a disorder of the executive function of both sensory and central nervous system. Recent studies suggest that immune mechanisms play a role in the pathophysiology of this disease. The variations in cytokine concentrations have been associated with psychopathology and treatment of schizophrenia. Objective: To investigate the changes in serum concentrations of TNF- α, IL-10, and IL-2 in schizophrenic patients before and 40 days after treatment. Methods: In a case-control study, 26 schizophrenic patients and 26 healthy individuals were enrolled as the control group. PANSS scale questionnaire was used for diagnosis and assessing the severity of the disease. All patients were then treated with risperidone or clozapine for 40 days. Serum concentrations of TNF- α, IL-10 and IL-2 were measured by ELISA before and after treatment in both groups. Paired t-test and Independent t-test were used for comparison of data. Results: Comparison of TNF-α and IL-10 concentrations in patients before and after treatment revealed a significance decrease of TNF- α and increase of IL-10 concentrations (p=0.002, and p=0.008, respectively). Serum concentrations of IL-2 were lower than the detection limit of assay and were not detectable. In comparison with healthy controls, serum concentrations of TNF- α in schizophrenic patients were higher, while IL-10 concentrations were lower before treatment although the differences were not significant (p=0.291 and p=0.375, respectively). There was no correlation between cytokine concentrations and the positive and negative scale (PANSS). Also no significant difference in the admission, relapses, and duration of illness before and after treatment was observed. Conclusions: Increase of TNF- α and decrease of IL-10 may have an important role inpsychopathology of schizophrenia.     

Phytic Acid Modulates In Vitro IL-8 and IL-6 Release from Colonic Epithelial Cells Stimulated with LPS and IL-1β

Phytic acid (PA), a major fiber-associated component of wheat bran and legumes, is physiologically present in the human large gut. The aim of this study was to examine the role of PA in immunologic function of intestinal epithelial cells by analyzing its effect on interleukin (IL)-8 and IL-6 secretion by colonocytes and its role in the response of these cells to bacterial lipopolysaccharides (LPS) and IL-1β. The human colon cell line Caco-2 was exposed to LPS isolated from two strains of Desulfovibrio desulfuricans, wild intestinal and type soil strains, as well as to LPS from E. coli. Cells were also treated with IL-1β and with a combination of LPS and IL-1β. PA had a suppressive effect on IL-8 basal release and it dose dependently reduced IL-8 secretion by colonocytes stimulated with LPS and IL-1β. On the contrary, PA increased constitutive IL-6 secretion and exhibited differentiated effects on LPS responsiveness of cells depending on its concentration and LPS origin. PA was also an efficient down-regulator of IL-6 secretion stimulated by binary actions of LPS and IL-1β. The ability of PA to modulate IL-8 and IL-6 release suggests that PA present in the intestinal milieu may exert immunoregulatory effects on colonic epithelium under physiological conditions or during microbe-induced infection/inflammation in order to maintain the colonic mucosa in a noninflammatory state or to counteract infection.     

Differential effect of IL-1β and TNF-α on the production of IL-6, IL-8 and PGE2 in fibroblast-like synoviocytes and THP-1 macrophages

Inflammation in the joint of rheumatoid arthritis is a complex immune reaction facilitated by various factors, such as cytokines, cells and hypoxia. Thus, we evaluated their relative capacity to produce proinflammatory mediators in response to IL-1β, TNF-α or IL-17 under hypoxia or normoxia in fibroblast-like synoviocytes (FLSs) and macrophages. The level of IL-6 expression was strongly increased in both FLSs and THP-1 macrophages in response to IL-1β and TNF-α, but the level by TNF-α was less than that by IL-1β. In contrast, the expression of IL-8 in both cell types was strongly stimulated by both IL-1β and TNF-α. In FLSs, PGE₂ production increased only in response to IL-1β; and no effect was observed in THP-1 cells and TNF-α-stimulated FLSs. In addition, the production by IL-17 was extremely low when compared with those induced by IL-1β or TNF-α in FLSs and THP-1 cells. Hypoxia (2% O₂) decreased IL-1β-stimulated production of PGE₂, even though it increased the expression of mRNA and protein of COX-2. These results suggest that IL-1β and TNF-α differentially regulate gene expression in FLSs and macrophages under hypoxia or normoxia.     

Clinical significance of IL-18, IL-15, IL-12 and TNF-α measurement in rheumatoid arthritis

The aim of the study was to evaluate the clinical significance of serum (S) and synovial fluid (SF) interleukin (IL)-18, IL-15, IL-12 and the tumor necrosis factor alpha (TNF-α) measurements in relation to laboratory and clinical measures of disease activity of patients with active rheumatoid arthritis (RA). Sixty-four patients with RA and 25 patients with osteoarthritis (OA) were included in this study. RA activity was determined using the Disease Activity Score (DAS) 28 index. Concentrations of IL-18, IL-15, IL-12 and TNF-α were measured by ELISA. Serum C-reactive protein (CRP) levels were also determined. Cross-sectional correlations between S and SF levels of cytokines and values of DAS 28 index were calculated. The results have shown that IL-18, IL-15, IL-12 and TNF-α levels in S and SF of patients with RA were significantly higher than the levels obtain from patients with OA (p<0.01). Significantly higher levels of IL-18, IL-15 and TNF-α were found in the SF compared to the S of patients with RA (p<0.01). Significantly higher S and SF levels of all four cytokines and serum CRP values were found in RA patients with high disease activity (DAS 28>5.1) compared to those with mild (DAS 28>3.2) and low disease activity (DAS 28>2.6) (p<0.01). Serum and SF concentrations of all four cytokines positively correlated with DAS 28 index values, i.e., disease activity. A poor correlation was found for S and SF IL-12 whereas the highest coefficient of correlation was found for SF IL-18 (r=0.879, p<0.01), and SF TNF-α (r=0.827, p<0.01) and disease activity in this study. Strong correlation was found between SF TNF-α and SF IL-18 levels (r=0.732, p<0.01). In conclusion, SF IL-18 and TNF-α levels in RA patients are good indicators of disease activity. The results obtained support the use of the DAS in clinical practice as a reliable method in assessing disease activity in RA patients.     

The TNF-α, IL-1B and IL-10 polymorphisms and risk for hepatocellular carcinoma: a meta-analysis

Objective  

TNF-α-308 G/A, TNF-α-238 G/A, IL-1B-31 T/C, IL-1B-511 C/T, and IL-10-1082 G/A polymorphisms have been reported to influence the risk for hepatocellular carcinoma (HCC) in many studies; however, the results still remains controversial and ambiguous. The aim of this study was to determine more precise estimations for the relationship between TNF-α, IL-1B, and IL-10 polymorphisms and the risk for HCC by meta-analysis.     

IL-10, TGF-ß, IL-2, IL-12, and IFN-γ Cytokine Gene Polymorphisms in Asthma

Asthma is a complex respiratory disease, characterized by airway inflammation and reversible airway obstruction. Both genetic and environmental factors are important in the development and expression of the disease. In order to analyze the genetic profile of Th1 and Th2 cytokines in Iranian asthmatic patients, this study was performed. The allele and genotype frequencies of a number of polymorphic genes coding for IL-10, TGF-ß, IL-2, IL-12, and IFN-γ were investigated in 60 patients with asthma in comparison with 140 controls. The most frequent genotypes in our patients were IL-10 GA at position-1082 (p = 0.001), IL-10 CT at position ?819 (p = 0.001), IL-10 CA at position ?592 (p = 0.0001), IL-12 CA at position ?1188 (p = 0.003), TGF-ß CG at codon 25 (p = 0.002), IL-2 GT at position -330 (p = 0.004). In contrast, the frequencies of the genotypes IL-10 AA at position ?1082 (p = 0.0001) and GG at position ?1082 (p = 0.01), IL-10 CC at position ?819 (p = 0.001) and TT at position -819 (p = 0.01), TGF-ß TT at codon 10 (p = 0.001), TGF-ß GG at codon 25 (p = 0.005), IL-12 AA at position ?1188 (p = 0.004), IL-2 TT at position ?330 (p = 0.01) were significantly lower in the patient group. The most frequent haplotypes in the patients were IL-10 GCC (p = 0.008) and ATA (p = 0.0001) at position ?1082, ?819, ?592, and TGF-ß CC (p = 0.036) at codon 10 and codon 25. In contrast, the frequencies of the IL-10 ACC (p = 0.001), TGF-ß TG (p = 0.024), and IL-2 TT (p = 0.001) and GT (p= 0.0001) in the patients were significantly lower than controls. Considering the high frequency of presence of IL-10 ATA haplotype and the IL-2 GT genotype, it seems that the production of IL-10 and IL-2 in the asthmatic patients could be lower than normal subjects.     

IL-1β and IL-8, matrix metalloproteinase 3, and pepsinogen secretion before and after H. pylori eradication in gastroduodenal phenotypes

Background: Adenomatous polyposis coli (APC) and β -catenin (encoded by CTNNB1 ) are important components in the WNT signalling pathway, a pathway altered in nearly all colorectal tumours. Conflicting results are reported on whether APC mutations are less common in tumours with a high degree of microsatellite instability (MSI-H) than in microsatellite stable (MSS) ones, and whether mutations in the regulatory domain of CTNNB1 substitute for APC mutations in the MSI-H tumours. Methods: A consecutive series of 218 primary colorectal carcinomas, stratified by MSI status, were analysed for mutations in the APC gene (by the protein truncation test) and in the CTNNB1 gene (by single-strand conformation polymorphism). Results: APC mutations detected in 66% of the patients were significantly more frequent in the MSS and MSI-L (low) tumours than in the MSI-H tumour group ( P < 0.001). The MSI-H tumours tended to have more frameshift mutations than the MSS/MSI-L tumours. The majority of the APC mutations were located in the mutation cluster region (MCR). Patients that had lost all β -catenin binding sites of the APC gene showed a shorter survival time than patients who retained some or all of these binding sites ( P = 0.045). Two mutations were found in the CTNNB1 gene, but neither of them was located in the regulatory domain in exon 3. Conclusion: This study confirms that APC mutations are less frequent in MSI-H tumours than in MSS and MSI-L tumours. However, CTNNB1 mutations do not substitute for APC mutations in MSI-H tumours in these Norwegian patients.     

The utility of TNF-α, IL-6 and IL-10 in the diagnosis and/or follow-up food allergy

BackgroundSeveral pro-inflammatory and anti-inflammatory mediators play a role in the immunopathogenesis of food allergy (FA). The aim of this study was to investigate the utility of serum biomarkers like interleukin (IL)-10, TNF-α, and IL-6 in the diagnosis and/or follow-up of FA.MethodsSixty (25 females, 41.6%) newly diagnosed FA patients [IgE mediated (group-1, n = 37), non-IgE (group-2, n = 23)] with a median age of nine (1–33) months were enrolled. Twenty-four healthy children with a median age of eight (1–36) months constituted the control group (CG). In all the subjects, serum TNF-α, IL-6 and IL-10 levels were evaluated at the time of diagnosis and reassessed four weeks after therapeutic elimination diet (TED).ResultsThe mean white blood cell count and median absolute eosinophile count of the CG were significantly lower than group-1 (p values were 0.019 and 0.006, respectively). The mean absolute neutrophile count and the median IL-6 were significantly higher in group-1 when compared with group-2 (p values were 0.005 and 0.032, respectively. Median TNF-α and IL-6 levels were significantly higher in the pre-TED among all patients (p values were 0.005 and 0.018, respectively). In group-1, median TNF-α and IL-6 levels decreased significantly after TED (p values were 0.01 and 0.029, respectively).ConclusionsOur findings support the role of inflammation in the pathogenesis of FA. Serum TNF-α and IL-6 levels may be useful markers for follow-up in FA, especially among IgE-mediated FA patients. Evaluation of IL-10 results was not sufficient for an interpretation of clinical tolerance.     

Inhibitors of p38 and ERK1/2 MAPkinase and hydrogen sulphide block constitutive and IL-1β-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2

Mitogen-activated protein kinases (MAPKs) play a central role in inflammatory processes, and their blockage represents pharmacological approaches in the treatment of autoimmune diseases like rheumatoid arthritis (RA). Alternatively, H₂S has long been used in sulphur bath therapy for patients suffering from different types of rheumatic disorders, but reports about the beneficial effects of this form of therapy are controversial, rare and of poor scientific quality. The human chondrocyte cell line C-28/I2 was treated with two different MAPK inhibitors (SB203580 and U0126) or with various concentrations of the H₂S donor Natrium hydrogen sulphide (NaHS). Thereafter, the secretion of IL-6 and IL-8 was quantified by enzyme-linked immunosorbent assays (ELISAs). The impact of NaHS on the regulation of p38 and ERK1/2 MAPK was confirmed by Western blot experiments. Furthermore, IL-6 and IL-8 expression was quantified by real-time polymerase chain reaction (RT-PCR) and ELISAs from cells which were exposed to SB203580, U0126 and NaHS and stimulated by IL-1β. The C-28/I2 cells constitutively expressed large quantities of IL-6 and IL-8. The data provided prove that in these cells, constitutive as well as IL-1β-induced IL-6 and IL-8 expression was partially and transiently blocked by the treatment of cells with both MAPK inhibitors and NaHS. Presented data seem to be important in evaluating the beneficial functions of MAPK inhibitors and H₂S in immune–pathophysiological processes.     

Preliminary analysis of single-nucleotide polymorphisms in IL-10, IL-4, and IL-4Rα genes and profile of circulating cytokines in patients with gastric Cancer

Background

Gastric Cancer is highly prevalent and deadly worldwide. In Colombia, it is the most lethal form of cancer. Some single-nucleotide polymorphisms in IL-10, IL-4, and IL-4Rα genes have been associated with an anti-inflammatory environment and a Th2 profile in detriment of the antitumor Th1 response. This research sought to detect single-nucleotide polymorphisms in promoter sequences, like ??1082 (G/A), ??592 (C/A), and???819 (C/T), as well as ??590 (C/T) of the IL-10 and IL-4 genes, respectively; in addition to the IL-4Rα mutation variants, Ile50Val and Q576R, together with circulating levels of IL-4, TNF-α, IL-10, and IFN-γ in patients with gastric carcinoma in Cúcuta, Colombia.

Methods

In a cross-sectional study, 17 patients and 30 healthy individuals were genotyped for the six polymorphisms mentioned through PCR-RFLP of DNA obtained from peripheral blood cells and serum samples were analyzed by sandwich ELISA to quantify cytokines. Statistical difference between groups was determined along with the association between the presence of polymorphisms and the risk of gastric cancer, as well as the mortality in patients, using Mann-Whitney U test and logistic regression analysis, respectively.

Results

An association between the ??1082 (G/A) and the risk of gastric cancer was found (OR?=?7.58, range 0.77–74.06, P?=?0.08). Furthermore, patients had a significant increase in IL-4 serum levels (P?<?0.01) compared to healthy individuals, both variables showed a higher estimated risk of mortality in patients, although without statistical association (P?>?0.05).

Conclusion

We infer that two possible biomarkers (one immunological and one genetic) could be considered in association with gastric cancer in our population, which should be confirmed by subsequent studies involving a greater number of individuals.

     

Expansion of human NK-22 cells with IL-7, IL-2, and IL-1β reveals intrinsic functional plasticity

Natural killer-22 (NK-22) cells are a human NK cell subset situated in mucosal-associated lymphoid tissues that specialize in IL-22 secretion in response to IL-23. Here we investigated the cytokine requirements for NK-22 cell expansion. IL-7 maintained the sur-vival of NK-22 cells and IL-22 production in response to IL-23 but was insufficient to induce robust expansion. Proliferation of NK-22 cells was increased markedly by adding either IL-1β or IL-2 to IL-7 and was even stronger in the presence of IL-1β plus IL-2. In contrast to IL-7, continuous culture in IL-1β and IL-2 modified NK-22 cytokine profiles. IL-1β promoted constitutive IL-22 secretion rather than acute IL-22 production in response to IL-23 and induced IL-17 in some cells. IL-2 reduced secretion of IL-22 and IL-17, increasing production of IFN-γ and leukemia inhibitory factor. Functional deviation toward IFN-γ production also was induced by continuous culture in IL-23. These results demonstrate the functional plasticity of NK-22 cells, which may allow flexible responses to different pathogens. Finally, we found that NK-22 cells released the B-cell survival factor, B-cell activating factor belonging to the TNF family (BAFF), suggesting a potential role of NK-22 cells in promoting B-cell–mediated mucosal immunity.     

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells,and in islets from pre-diabetic NOD mice

AIMS/HYPOTHESIS: Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1beta and IFN-gamma have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3alpha, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation. METHODS: FACS-purified rat beta cells and human islets were cultured with IL-1beta, IFN-gamma and/or TNF-alpha. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2- or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA. RESULTS: Human islets and rat beta cells express IP-10, MIP-3alpha, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-gamma, while the expression of MIP-3alpha is IL-1beta-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3alpha protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3alpha expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1beta, IFN-gamma, fractalkine, IP-10, MCP-1 and MIP-3alpha mRNAs were observed in the grafts. CONCLUSION/INTERPRETATION: Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction.     

PAF effects on MCP-1 and IL-6 secretion in U-937 monocytes in comparison with oxLDL and IL-1β effects

Objective

To study the effects of PAF, in comparison with OxLDL and IL-1β on MCP-1 and IL-6 secretion from U-937 monocytes and to investigate the mechanism of its action.

Methods

U-937 cell line was cultured in the presence or absence of PAF or OxLDL or IL-1β. Secretion of IL-6 and MCP-1 was measured by ELISA method, mRNA levels of MCP-1 and PAFR was measured using real-time PCR. In order to investigate the mechanism of mediator's action signal transduction appropriate inhibitors was used and oxidant status of cells by measurement the total cellular thiols content and glutathione was determined.

Results and conclusion

None of the tested mediators induced the secretion of IL-6. On the other hand PAF and OxLDL caused a short-term while IL-1β caused a long-term secretion and expression of MCP-1. Reduced total thiol levels and GSH/GSSG ratio indicate that the above mediators induce oxidative stress. The signal transduction of all mediators is mediated through G-proteins, protein kinases (PKC, serine–threonine kinase and tyrosine kinase) and NF-κB activation. In addition, PAF, OxLDL, IL-1β activates monocytes leading to increased PAF receptor mRNA levels. These results indicate that PAF and OxLDL, in a different pattern from that of IL-1β, regulate MCP-1 expression via pathways that involve changes in cell redox status.     

IL-1β and IL-6 in community-acquired pneumonia: Bacteremic pneumococcal pneumonia versusMycoplasma pneumoniae pneumonia

Summary Interleukin-1 (IL-1) and interleukin-6 (IL-6) levels in 20 patients with bacteremicStreptococcus pneumoniae community-acquired pneumonia (CAP) were compared with these cytokine levels in 20 patients withMycoplasma pneumoniae CAP. All 40 patients survived hospitalization and underwent a follow-up examination one month later. Serum IL-1 and IL-6 levels were determined by the enzyme immunoassay (EIA) method using commercial kits. In the acute phase of CAP, IL-6 levels were significantly higher in theS. pneumoniae group (p=0.014), while IL-1 levels were higher in theM. pneumoniae group (p=0.046). In the convalescence phase, the two cytokines were detected in a considerable number of patients in both groups. In this phase, only the level of IL-1 was significantly higher in theM. pneumoniae group than in theS. pneumoniae group (p=0.03). We conclude that the levels of IL-1 and IL-6 are different between patients withS. pneumoniae-CAP andM. pneumoniae-CAP during the acute phase. In the convalescence phase, cytokine levels remain high in some of the CAP patients, but a significant difference between the groups exists only for IL-1. Further studies are required.     

Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα

Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Rα levels in human T1D. To investigate the role of IL-15/IL-15Rα in the pathogenesis of T1D, we generated double transgenic mice with pancreatic β-cell expression of IL-15 and IL-15Rα. The mice developed hyperglycemia, marked mononuclear cell infiltration, β-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15Rβ (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15Rα expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15Rα in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Rα may be involved in T1D pathogenesis and the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing β cells in pancreatic islets are destroyed by autoreactive T cells. During prolonged lack of insulin, blood glucose increases (hyperglycemia) and tissue damage occurs. Studies in animal models and humans demonstrated that β-cell destruction is usually accompanied by inflammation of pancreatic islets (insulitis), which suggests that activation of inflammatory T cells is important in the development of diabetes (1, 2). What triggers the T-cell infiltrate into the islets and subsequent β-cell destruction? What signaling pathways are important for this process? An understanding of the molecular events and signaling pathways that lead to T-cell activation and subsequent β-cell destruction would be useful in the development of new therapeutics for autoimmune T1D.Interleukin-15 (IL-15) is a proinflammatory cytokine that promotes the activation and maintenance of natural killer (NK) and CD8 (+) T-effector memory (T-EM) cells (3, 4). IL-15R alpha (IL-15Rα), the high affinity private receptor for IL-15, stabilizes and chaperons IL-15 on dendritic cell membrane and activates neighboring NK and T cells via transpresentation (5–8). Therefore, IL-15 is not secreted; rather, it is a membrane-associated molecule that acts as part of an immunological synapse (5, 6, 8). During an immune response such as viral infection, IL-15 and its private receptor IL-15Rα are coordinately induced (5, 8, 9). As related to T1D, it has been shown that exposure of human pancreatic islets to coxsackie virus, an enterovirus linked to T1D, or directly to IFNγ induced high gene expression of IL-15 and IL-15Rα in the islets in vitro (10).Abnormal expression of IL-15 has been reported in many autoimmune disorders including rheumatoid arthritis, celiac disease, psoriasis, inflammatory bowel disease, and multiple sclerosis (11). In patients with T1D, elevated serum levels of IL-15 have been reported (12). Using a unique assay we developed for soluble IL-15Rα (sIL-15Rα) (13), we discovered elevated serum levels of sIL-15Rα in T1D.To investigate whether islet overexpression of IL-15 and IL-15Rα could play a role in the pathogenesis of T1D, we generated double transgenic mice with β-cell–specific expression of both IL-15 and IL-15Rα under a rat insulin promoter (RIP). The mice developed hyperglycemia, marked mononuclear cell infiltration, β-cell destruction, and anti-insulin autoantibodies that mimic the early events of human T1D. Inhibiting IL-15/IL-15Rα signaling either by blocking IL-15 transpresentation using TMβ1, a monoclonal antibody that is directed to IL-2/IL-15Rβ (CD122) or by blocking IL-15 signaling by administration of the Janus kinase 2/3 (Jak2/3) inhibitor tofacitinib reversed the diabetes in the double transgenic mice. Moreover, in another diabetes mouse model, nonobese diabetic (NOD) mice, increased islet cell expression of IL-15 and IL-15Rα were found at the prediabetic stage and the inhibition of IL-15 signaling delayed the diabetes development. Considering viral infection and interferons are often found in the pancreatic islets of patients with T1D (14–16), and they are potent inducers of IL-15/IL15Rα (9, 17–19), we investigated whether IL-15 and IL-15Rα were expressed in the islets of patients with T1D. Our data demonstrated increased expression of both IL-15 and IL-15Rα in the islets of patients with T1D. Taken together, our data suggest that the disordered expression of IL-15/IL-15Rα in islets may play a role in the pathogenesis of T1D and that the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.