Interleukin-19 protects mice from innate-mediated colonic inflammation.
ABSTRACT Inflammatory bowel disease (IBD) results from the chronic dysregulation of the mucosal immune system and the aberrant activation of both the innate and the adaptive immune responses. We used two complementary models of colonic inflammation to examine the roles of interleukin (IL)-19 in colonic inflammation and thus its possible role in IBD.
Using gene-targeting, we generated IL-19-deficient mice. To study the activation of the innate immune response during colonic inflammation we characterized an innate immune-mediated model of colitis induced by dextran sulfate sodium (DSS). DSS can induce not only acute colitis but also chronic colitis. In addition to the acute DSS-induced colitis model, we used a chronic DSS-induced colitis model that is associated with the activation of both Th1 and Th2 cytokines as well as innate immune response in the colon.
We show that IL-19-deficient mice are more susceptible to experimental acute colitis induced by DSS, and this increased susceptibility is correlated with the accumulation of macrophages and the increased production of IFN-gamma, IL-1beta, IL-6, IL-12, TNF-alpha, and KC. Additionally, cytokine production in IL-19-deficient macrophages was enhanced on stimulation of lipopolysaccharide (LPS) through reduced phosphorylation of STAT1 and STAT3. Moreover, our results clearly demonstrate that IL-19 is required for B-cell infiltration during chronic DSS-induced colitis, which may be mediated by IL-13 and IL-6.
The finding that IL-19 drives pathogenic innate immune responses in the colon suggests that the selective targeting of IL-19 may be an effective therapeutic approach in the treatment of human IBD.
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ABSTRACT: There is increasing evidence to suggest that the newly discovered cytokines interleukin (IL)-19 and -20 have a role in the function of epidermis and in psoriasis. The genes encoding these cytokines locate into the genomic IL-10 region on human chromosome 1. The aim of the present study was to analyze whether single-nucleotide polymorphisms (SNPs) in these genes have an impact on the susceptibility for psoriasis. From pairwise linkage disequilibrium (LD) matrix of the IL-19 and -20 gene polymorphisms, what reflects the nonrandom association of alleles at these markers, it was apparent that IL-19 and -20 genes form one block of LD. We found that the HT3 CACCGGAA haplotype of the IL-19 and -20 genes was associated with an increased risk of psoriasis, reflecting its role in determining susceptibility to plaque-type psoriasis. Although association analysis of the IL-19 gene indicated that minor alleles of the IL-19 gene SNPs (rs2243188, rs2243169 and rs2243158) revealed protective effect to psoriasis and haplotype analysis of the IL-19 gene proved significant protective effect of the TGATA haplotype in case of late-onset disease, combined haplotype analysis of the IL-19 and -20 genes demonstrated that protective effect of the IL-19 gene is secondary to the susceptibility effect of the IL-20 gene.Genes and Immunity 01/2005; 5(8):662-7. · 3.68 Impact Factor
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ABSTRACT: IL-10 is an immunosuppressive cytokine in the immune system. It was in clinical trial as an anti-inflammatory therapy for inflammatory bowel disease and various autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis. IL-19 belongs to the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiation-associated gene (MDA-7, IL-24), and AK155 (IL-26). Despite a partial homology in their amino acid sequences, they are dissimilar in their biologic functions. Little is known about the biologic function and gene regulation of IL-19. To understand the gene regulation of human IL-19, we identified a human IL-19 genomic clone and analyzed its promoter region. Five fusion genes containing different regions upstream of exon 1 linked to a luciferase reporter gene were expressed in the canine kidney epithelial-like Madin-Darby canine kidney cells. A fusion gene containing 394 bp showed luciferase activity 7- to 8-fold higher than the negative control of the promoterless fusion gene. We also isolated a full-length mouse cDNA clone. Mouse IL-19 shared 71% amino acid identity with human IL-19. Treatment of monocytes with mouse IL-19 induced the production of IL-6 and TNF-alpha. It also induced mouse monocyte apoptosis and the production of reactive oxygen species. Taken together, our results indicate that mouse IL-19 may play some important roles in inflammatory responses because it up-regulates IL-6 and TNF-alpha and induces apoptosis.The Journal of Immunology 11/2002; 169(8):4288-97. · 5.52 Impact Factor
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ABSTRACT: Patients with end-stage renal disease are thought to be in a chronic state of inflammation. They also have an impaired immune response with a dysregulated Th1/Th2 cytokine network. Interleukin (IL)-19, which belongs to the IL-10 family, is a newly discovered proinflammatory cytokine. IL-19 alters the balance of Th1/Th2 cells in favour of Th2. The aims of the present study were to assess the changes in serum levels of IL-19 and their correlation with Th2 cytokine production in uraemic patients. Seventy-three uraemic patients with haemodialysis were evaluated; 33 healthy volunteers served as controls. Serum levels of IL-19, -4, -5, -6, -10, -13 and tumour necrosis factor (TNF)-alpha were analysed using ELISA. Monocytes and T cells isolated from the patients and healthy volunteers were cultured in vitro, and cytokine production was determined. IL-19 expression in the patients; but not in healthy controls, correlated positively with both the proinflammatory cytokines (IL-6 and TNF-alpha) and the Th2 cytokines (IL-4, IL-5, IL-6, IL-10 and IL-13). Cultured monocytes from patients with high IL-19 serum levels produced more IL-19 in vitro. Additionally, uraemic serum or oxidized low-density lipoproteins up-regulated the IL-19 transcripts expression in resting monocytes. Compared with T cells from healthy controls, uraemic T cells expressed more endogenous Th2 cytokine transcripts and further responded to IL-19 stimulation in Th2 cytokine production in vitro. IL-19 expression in uraemic patients correlated with Th2 immune responses which might be involved in the cytokine dysregulation in uraemia.Nephrology Dialysis Transplantation 09/2007; 22(8):2230-8. · 3.37 Impact Factor