The beneficial effects of localized tumor necrosis factor production in BCG infection.

Inflammatory responses to infectious agents involve different cell populations, including monocytes/macrophages, granulocytes, eosinophils, mastocytes and lymphocytes, which realize a cooperative network aimed at microbial clearance. The recruitment and activation of these inflammatory cells is mediated by a series of cytokines synthesized by distinct elements of the immune system. In particular, the production of tumor necrosis factor (TNF) is known to be induced during the course of various infectious processes. TNF is now recognized to be the major effector of gram-negative endotoxic shock. Experimental and clinical studies have documented the systemic release of TNF during bacterial and parasitic infections, and TNF is considered to account for some of the severe metabolic and tissular damages associated with such disease states. In contrast, we have shown that during BCG infections TNF is produced transiently and focally by granulomas in response to mycobacterial challenge and that it contributes to their containment and elimination. These observations suggest that the localized release of TNF may play a pivotal role in defense mechanisms against microorganisms, while its overproduction, leading to systemic release during severe infections, might be held responsible for a wide range of tissular injuries.