Abstract
Background: IL-19 is a member of the IL-10 family and produced by mainly macrophages, keratinocytes, epithelial cells, B cells, and vascular smooth muscle cells. However, little is known about the exact immunological role of IL-19 in the systemic inflammatory diseases in vivo. Inflammatory bowel disease results from chronic dysregulation of the mucosal immune system involving aberrant activation of innate and adaptive immune responses. Here, using gene-targeting, we have identified a novel role for IL-19 as a regulator in colonic inflammation.
Methods: C57BL/6 genetic background IL-19 knockout (KO) mice were used. Mice received oral administration of dextran sodium sulfate (DSS), a sulfated polysaccharide that can disrupt the mucosal epithelial barrier, thereby exposing local macrophages to pathogenic stimuli from the intestinal microflora. The colitis was evaluated by analyzing mortality, the disease activity index (DAI), and histology of the distal colon. Clinical scores for weight loss, bleeding and diarrhea resulted in the DAI. Bone marrow-derived macrophages were cultured in vitro to determine cytokine production.
Results: IL-19 KO mice showed severe mortality on administration of 3% DSS in drinking water for 7 days compared with wild-type (WT) mice. In accordance with the observed difference in survival, IL-19 KO mice showed much more severe weight loss. IL-19 KO mice had a significantly higher DAI score compared with WT mice on day 4 to day 8. Histological analysis revealed that the distal colons of IL-19 KO mice showed an increased number of infiltrating cells and a general loss of architecture, including extensive damage to both goblet and epithelial cells. The distal colon of IL-19 KO mice produced extremely high levels of IL-1beta, IL-6, IL-12, IFN-gamma, and TNF-alpha on day 5 after DSS administrations. Additionally the distal colon of IL-19 KO mice contained a high level of F4/80-pisitive cells. Bone marrow-derived macrophages from IL-19 KO mice produced significantly higher levels of IL-6, TNF-alpha and IL-12 than macrophages from WT mice following stimulation with LPS in vitro.
Conclusions: Our findings indicate that IL-19 has previously undocumented roles in the protection of mucosal epithelial cells and the elimination of acute inflammation in the colon.
