Role of T-cell Produced Interleukin-10 in the Control of Polyp Growth in the Small Intestine Versus Colon.

摘要

Interleukin (IL)-10 is elevated in colon cancer and can promote tumor growth by inhibiting anti-tumor immunity, or it can suppress progression by limiting excessive tumor-promoting inflammation. Patients with a mutation to the adenomatous polyposis coli (APC) gene develop familial adenomatous polyposis, a syndrome in which hundreds of pre-cancerous polyps form in the colon, strongly predisposing the patient to colon cancer.;Mouse models with a defective allele of APC are used to study colon cancer. Murine polyposis requires local inflammatory reactions and is associated with elevated levels of IL-10. We tested the role of CD4+ T-cell-produced IL-10 in small intestinal and colonic polyposis by rendering APCDelta468 mice defective for CD4+ T-cell-produced IL-10. Our studies have found that elevated levels of IL-10 are protective. Loss of IL-10 leads to decreased anti-tumor immunity and worse disease outcome.;We found that CD4+ T-cells are the major producers of IL-10 in the intestinal mucosa, and that the frequency of these cells is elevated in polyposis. In addition, we found that CD4+ T-cell production of IL-10 was critically required for the increase in tissue levels of IL-10 associated with polyposis.;Loss of T-cell IL-10 led to increased intra-polyp bacterial load and focal inflammation in the colon, significantly increasing polyp frequencies. Antibiotic treatment prevented this effect. In the same mice, small intestinal polyps had delayed growth compared to IL-10-proficient mice, however the polyps progressed to cancer. Small intestinal polyps differed from colonic polyps in the type of focal inflammation, and their growth was resistant to antibiotics. Furthermore, the inability of T-cells to produce IL-10 hampered T-helper-1 (TH1) commitment of CD4+ T-cells and interrupted the duration of intra-polyp cytotoxic activity.;Our findings highlight a critical role of T-cell-produced IL-10 in the regulation of inflammation and polyposis in the small intestine and colon. Colonic polyposis is driven by intra-polyp inflammatory reactions, which are tuned by microbial communities within the polyps and by infiltrating T-cells. In contrast, T-helper responses and cytotoxic activity play major roles in regulating growth of polyps and controlling their transition to cancer in the small intestine, and expression of IL-10 by T-cells critically contributes to both.