Lack of APC-derived IL-10 contributes to the pathogenesis of colitis in IL-10 deficient mice | Posted on:2004-01-18 | Degree:Ph.D | Type:Dissertation | University:The University of North Carolina at Chapel Hill | Candidate:Albright, Carol | Full Text:PDF | GTID:1454390011957170 | Subject:Biology | Abstract/Summary: | | Interleukin-10 deficient (IL-10−/−) mice develop chronic colitis when colonized with normal commensal bacteria, slowly progressing colitis when selectively colonized with nonpathogenic Enterococcus faecalis, and no disease under germ-free (GF) conditions. Antigen presenting cells (APC) process and present antigens to T lymphocytes and secrete regulatory cytokines which help determine activation or tolerance. Dendritic cells (DC) are the most potent APC based on their unique ability to stimulate naïve T cells. We used an in vitro culture system and in vivo transfer experiments to assess the function of IL-10 from APC in the pathogenesis of colitis.; In vitro we demonstrated that CD4+ T cells from mesenteric lymph nodes of inflamed IL-10−/− mice secrete more IFNγ when cultured with cecal bacterial lysate (CBL)-pulsed IL-10−/− APC than when cultured with CBL-pulsed normal APC. Only IL-10−/− APC produced IL-12. CBL-pulsed normal APC cultured with activated CD4 + cells from colitic IL-10−/− mice or with exogenous IFNγ secrete higher amounts of IL-10 compared to APC cultured with normal T cells. When both IL-10−/− and normal APC were enriched for CD11c + cells, a DC marker, the induction of IFNγ in CD4+ cells increased.; To assess the role of IL-10−/− DC in vivo, we transferred antigen-pulsed DC into GF IL-10−/− mice subsequently monoassociated with E. faecalis. Spleen-derived cultured IL-10−/− DC were pulsed in vitro with E. faecalis lysate or ovalbumin (OVA), then injected into GF IL-10−/− mice. One week later mice were monoassociated with E. faecalis. More aggressive colitis developed in recipients of E. faecalis-pulsed DC than in OVA-pulsed DC controls or untreated E. faecalis monoassociated IL-10−/− mice. Recipients of E. faecalis -pulsed DC exhibited enhanced bacterial antigen-specific CD4 + T cell responses.; We conclude that endogenous IL-10, produced by APC, inhibits APC responses to commensal bacteria and regulates IFNγ-producing effector lymphocytes, while IFNγ produced by activated T cells stimulates IL-10 production by APC. Adoptive transfer of E. faecalis-pulsed IL-10−/− DC accelerated the onset of colitis in IL-10−/− mice monoassociated with E. faecalis. These results illustrate the key role for APC activated by luminal bacteria in initiating T cell dependent intestinal inflammation and for IL-10 producing APC in inhibiting pathogenic T cell responses. | Keywords/Search Tags: | APC, IL-10, Mice, Colitis, Bacteria, Cells, Faecalis | | Related items |
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