Interleukin-19 protects mice from innate-mediated colonic inflammation. Inflamm Bowel Dis

Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, Izumisano, Osaka 598-8531, Japan.
Inflammatory Bowel Diseases (Impact Factor: 4.46). 06/2010; 16(6):1017-28. DOI: 10.1002/ibd.21151
Source: PubMed

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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    • "It is also involved in the pathogenesis of psoriasis [10], [11], neoplastic processes [12], [13], endotoxic shock [14], chronic rhinosinusitis [15], vascular disease [16], [17], [18], and rheumatoid arthritis [19], [20], [21]. Regarding IL-19 effects in vivo, Azuma et al. [22] reported that IL-19-deficient mice are more susceptible to experimental acute colitis induced by dextran sodium sulfate (DSS) than wild type (WT) mice. Crohn’s disease (CD) is an inflammatory bowel disease (IBD). "
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    ABSTRACT: The exact function of interleukin-19 (IL-19) on immune response is poorly understood. In mice, IL-19 up-regulates TNFα and IL-6 expression and its deficiency increases susceptibility to DSS-induced colitis. In humans, IL-19 favors a Th2 response and is elevated in several diseases. We here investigate the expression and effects of IL-19 on cells from active Crohn's disease (CD) patient. Twenty-three active CD patients and 20 healthy controls (HC) were included. mRNA and protein IL-19 levels were analyzed in monocytes. IL-19 effects were determined in vitro on the T cell phenotype and in the production of cytokines by immune cells. We observed that unstimulated and TLR-activated monocytes expressed significantly lower IL-19 mRNA in active CD patients than in HC (logFC = -1.97 unstimulated; -1.88 with Pam3CSK4; and -1.91 with FSL-1; p<0.001). These results were confirmed at protein level. Exogenous IL-19 had an anti-inflammatory effect on HC but not on CD patients. IL-19 decreased TNFα production in PBMC (850.7±75.29 pg/ml vs 2626.0±350 pg/ml; p<0.01) and increased CTLA4 expression (22.04±1.55% vs 13.98±2.05%; p<0.05) and IL-4 production (32.5±8.9 pg/ml vs 13.5±2.9 pg/ml; p<0.05) in T cells from HC. IL-10 regulated IL-19 production in both active CD patients and HC. We observed that three of the miRNAs that can modulate IL-19 mRNA expression, were up-regulated in monocytes from active CD patients. These results suggested that IL-19 had an anti-inflammatory role in this study. Defects in IL-19 expression and the lack of response to this cytokine could contribute to inflammatory mechanisms in active CD patients.
    PLoS ONE 04/2014; 9(4):e93910. DOI:10.1371/journal.pone.0093910 · 3.23 Impact Factor
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    • "Recent studies have shown that IL-19 is produced by keratinocytes (Kunz et al., 2006), epithelial cells (Zhong et al., 2006), macrophages (Azuma et al., 2010), B cells (Wolk et al., 2002), and vascular smooth muscle cells (Tian et al., 2008). IL-19 is involved in chronic inflammation and autoimmune diseases, such as psoriasis (Otkjaer et al., 2005; Romer et al., 2003), inflammatory bowel disease (Azuma et al., 2010), and asthma (Huang et al., 2008; Liao et al., 2004). Previous studies have shown that IL-19 is associated with the development of Th2 responses and alters the Th1/Th2 balance in the adaptive immune system. "
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    ABSTRACT: Genome-wide association studies (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with multifactorial diseases, such as schizophrenia, are significantly more likely to be associated with expression quantitative trait loci (eQTL). It was recently suggested that an immune system imbalance plays an important role in the pathogenesis of schizophrenia. Interleukin-19 is a novel cytokine that may play multiple roles in immune regulation and various diseases. We selected eight tag SNPs in the eQTL of the IL-19 gene. Seven of the SNPs are putative cis-acting SNPs. Then, we conducted a case-control study using two independent samples. The first sample comprised 567 schizophrenia patients and 710 controls, and the second sample comprised 677 schizophrenia patients and 667 controls. We identified the TGAA haplotype as being significantly associated with schizophrenia (p=0.0036 and corrected p=0.0264), although a combined analysis of the TGAA haplotype with the replication samples exhibited a nominally significant difference (p=0.022 and corrected p=0.235). These results suggest that the IL-19 gene might slightly contribute to the genetic risk of schizophrenia. Thus, further research on the association of eQTL SNPs with schizophrenia is warranted.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2013; 50. DOI:10.1016/j.pnpbp.2013.12.006 · 3.69 Impact Factor
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    • "Furthermore, antigens of Ascaris suis and E. histolytica elicited strong chemotaxis and production of superoxide anions in neutrophil granulocytes [23,24]. IL-19 is a member of the IL-10 family; secreted by monocytes, epithelial cells and B cells [25-27], it exerts regulatory effects and, in mice, protects against colonic inflammation [28] and induces Th2 responses [29]. Inducible cellular IL-19 production in adults and elderly could therefore mirror an adaptation to intestinal protozoan and metazoan parasite challenge and allergen exposure over time. "
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    Immunity & Ageing 07/2013; 10(1):29. DOI:10.1186/1742-4933-10-29 · 3.54 Impact Factor
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