Growth inhibition of Mycobacterium bovis by IFN-γ stimulated macrophages: regulation by endogenous tumor necrosis factor-α and by IL-10

Abstract

Murine bone marrow-derived macrophages (BMM) are able to inhibit the intracellular growth of Mycobacterium bovis and Mycobacterium tuberculosis H37Rv after activation with recomblnant (r) IFN and growth inhibition is mediated by reactive nitrogen intermediates (RNI) derived from L-arglnlne. We now demonstrate that tumor necrosis factor (TNF)-α acts as an endogenous cofactor in the induction of mycobacterial growth inhibition. TNF-α was produced by BMM stimulated with rlFN-γ and infected with mycobacterla, and a specific antlserum to TNF-α Inhibited rlFN-γ-lnduced production of RNI as well as growth inhibition of M. bovis. IL-10, a cytokine which suppresses antlmycobacterial macrophage functions, was also produced by BMM activated with hFN-γ and infected with M. bovis. IFN-γ-induced production of TNF-α and of reactive nitrogen intermediates as well as mycobacterial growth inhibition were inhibited by exogenous IL-10, but only when given prior to IFN-γ stimulation. We conclude that the outcome of mycobacterial infection is regulated by a coordinate interplay between IFN-γ, TNF-α and IL-10.