Mitogen-activated protein kinases regulate Mycobacterium avium-induced tumor necrosis factor-α release from macrophages

Abstract

Tumor necrosis factor-α (TNF-α) is one of the key cytokines elicited by host macrophages upon challenge with pathogenic mycobacteria. Infection of human peripheral blood mononuclear cells or the murine macrophage cell line J774A-1 with Mycobacterium avium induced activation of the mitogen-activated protein kinases (MAPKs) ERK ½, p38 and c-Jun N-terminal kinase. U0126, an MEK-specific inhibitor, abrogated M. avium-induced TNF-α secretion. Transfection of cells with dominant-negative MEK1 led to the suppression of TNF-α release in M. avium-challenged macrophages. M. avium activated p38 MAPK and use of the p38 MAPK inhibitor, SB203580, revealed that the p38 signaling pathway negatively regulates activation of ERK½ and release of TNF-α. Taken together, these results provide evidence that M. avium-induced TNF-α release from macrophages depends on an interplay between the ERK½ and the p38 MAPK signaling pathways.