Nitric oxide dependent killing of Mycobacterium tuberculosis by human mononuclear phagocytes from patients with active tuberculosis

Abstract

In this study we have demonstrated that nitric oxide, the product of the arginine dependent pathway of human mononuclear phagocytes effectively kills the M.tuberculosis in-vitro. The release of reactive nitrogen intermediates was triggered by incubation with various proinflammatory cytokines namely IFN-γ, TNF-α and IL-1β. We have earlier shown that human mononuclear phagocytes can be induced to release nitric oxide (NO) radicals which can kill tumour cells. In the present communication, by using colony forming assays we demonstrated that human mononuclear phagocytes can effectively kill M.tuberculosis by using a NO dependent pathway. Treatment of mononuclear phagocytes with L-arginine resulted in markedly increased killing activity whereas, by using NGMMA, an analogue of L-arginine, the cidal activity could be brought down to the basal level. These results clearly suggest that cytokines, particularly IFN-γ, induced NO release and its reactive product with oxygen radical, peroxynitrite, could play an important role in the killing of M. tuberculosis by human mononuclear phagocytes. A significant production of interleukin-4 and interleukin-10, by the ex-vivo matured, untreated macrophages from the active tuberculosis patients indicate that regulation of cytokine network to encourage in situ/local production of nitric oxide may be useful in the management of pulmonary tuberculosis.