Inducible Nitric Oxide Synthase From Bone Marrow-Derived Cells Plays a Critical Role in Regulating Colonic Inflammation

Background & Aims: Nitric oxide (NO) is an important mediator of intestinal inflammation. Inducible NO synthase (iNOS) is the main source of NO in inflammation. Because iNOS is ubiquitously expressed, our aim was to determine which cellular source(s) of iNOS plays the central role in mediating intestinal inflammation. Methods: Chimeric lines were produced via bone marrow (BM) transplantation following irradiation. Colitis was induced with dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS). The severity of colitis and markers of inflammation were assessed in standard fashion. Leukocyte recruitment was assessed by intravital microscopy. Results: The irradiated chimeric lines with iNOS−/− BM-derived cells were markedly more resistant to both DSS- and TNBS-induced injury. Resistance to DSS-induced colitis was lost when wild-type (wt) BM was used to reconstitute iNOS−/− mice. Neutrophils were the main source of iNOS in DSS-induced colitis. iNOS−/− chimeric lines had decreased colonic macrophage inflammatory protein 1β and tumor necrosis factor α expression and increased levels of the protective growth factor, keratinocyte growth factor. LPS-mediated leukocyte recruitment was reduced in iNOS−/− mice, and there were marked changes in the inflammatory cell infiltrates between the chimeric lines with iNOS−/− vs wt BM-derived cells. Furthermore, the lamina propria CD4 +ve cells from chimeric lines with iNOS−/− BM-derived cells had reduced intracellular cytokine expression. Conclusions: iNOS produced by BM-derived cells plays a critical role in mediating the inflammatory response during colitis. Cell-specific regulation of iNOS may represent a novel form of therapy for patients with inflammatory bowel disease.