Interleukin-19 protects mice from innate-mediated colonic inflammation

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: 5.48). 01/2010; 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TFF2 is a member of a tripartite family of small proteins, produced by the stomach and the colon. Recombinant TFF2, when applied intra-rectally in a rodent model of hapten colitis, both hastens mucosal healing and reduces inflammatory indices. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel. In this study we confirm that TFF2 is expressed in the colon and is specifically enriched in epithelial cells relative to colonic leucocytes. TFF2, but not TFF1 null mice have a more severe response to acute or chronic dextran sulphate (DSS)-induced colitis that correlates with a 50% loss in TFF3 expression, the principle colonic trefoil. In addition, the response to acute colitis is associated with altered expression of IL-6 and IL-33, but not other inflammatory cytokines. While TFF2 can reduce macrophage responsiveness and block inflammatory cell recruitment to the colon, the major role in limiting the susceptibility to acute colitis appears to be by maintaining barrier function. Bone marrow transfer experiments demonstrate that leukocyte expression of TFF2 is not sufficient for prevention of colitis induction rather that the gastrointestinal epithelium is the primary source of TFF2. Together this data illustrates that epithelial TFF2 is an important endogenous regulator of gut mucosal homeostasis, which can modulate both immune and epithelial compartments. The extreme stability of TFF2 even in the corrosive gut lumen makes this protein an attractive candidate as an oral therapeutic scaffold for future drug development in the treatment of inflammatory bowel disease.
    AJP Gastrointestinal and Liver Physiology 10/2014; DOI:10.1152/ajpgi.00172.2014 · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The purpose of this study was to evaluate whether a single-nucleotide polymorphism (SNP), rs2243188 of interleukin-19 (IL-19), show significant evidence for association with SLE in a Chinese population. A total of 545 SLE patients and 613 healthy controls were collected in the present study. The genotyping of IL-19 rs2243188 polymorphism was detected by TaqMan allele discrimination assay on the 7300 real time polymorphism chain reaction system. The minor C allele of rs2243188, relative to the major A allele, appeared to have a significantly lower frequency in SLE patients (31.0%) as compared with controls (35.5%) (χ(2) = 5.19, p = 0.023). We also discovered a statistical significance in the dominant model (CC + CA versus AA: OR = 0.755, 95% CI = 0.598-0.953, p = 0.018). However, no significant difference in genotype distribution was found between SLE patients and controls (p = 0.056). Furthermore, an increased frequency of CC genotype were also detected in lupus nephritis (LN) groups as compared with non-LN groups (p = 0.024). Besides, the individuals with CC genotype had a 2.201-fold higher risk for the susceptibility to LN than those A allele carriers (AA + CA) (p = 0.006). Unfortunately, the analyses on the relationship of IL-19 rs2243188 with several clinical manifestations of SLE failed to find any significant results. In conclusion, our observations suggested the minor C allele of SNP rs2243188 might be a protective factor for SLE in a Chinese Han population. Moreover, the subgroup analysis highlighted that IL-19 rs2243188 SNP was associated with the susceptibility to LN patients.
    Autoimmunity 05/2014; DOI:10.3109/08916934.2014.914505 · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that IL-19, a putative member of the type 2 helper T-cell family of anti-inflammatory interleukins, can attenuate intimal hyperplasia and modulate the vascular smooth muscle cell (VSMC) response to injury. Ligated carotid artery of IL-19 knockout (KO) mice demonstrated a significantly higher neointima/intima ratio compared with wild-type (WT) mice (P = 0.04). More important, the increased neointima/intima ratio in the KO could be reversed, or rescued, by injection of 10 ng/g per day recombinant IL-19 into the KO mouse (P = 0.04). VSMCs explanted from IL-19 KO mice proliferated significantly more rapidly than WT. This could be inhibited by addition of IL-19 to KO VSMCs (P = 0.04 and P < 0.01). IL-19 KO VSMCs migrated more rapidly compared with WT (P < 0.01). Interestingly, there was no type 1 helper T-cell polarization in the KO mouse, but there was significantly greater leukocyte infiltrate in the ligated artery in these mice compared with WT. IL-19 KO VSMCs expressed significantly greater levels of inflammatory mRNA, including IL-1β, tumor necrosis factor α, and monocyte chemoattractant protein-1 in response to tumor necrosis factor α stimulation (P < 0.01 for all). KO VSMCs expressed greater adhesion molecule expression and adherence to monocytes. Together, these data indicate that IL-19 is a previously unrecognized counterregulatory factor for VSMCs, and its expression is an important protective mechanism in regulation of vascular restenosis.
    American Journal Of Pathology 05/2014; DOI:10.1016/j.ajpath.2014.04.001 · 4.60 Impact Factor