PATHOGENIC MYCOBACTERIUM-TUBERCULOSIS EVADES APOPTOSIS OF HOST MACROPHAGES BY RELEASE OF TNF-R2, RESULTING IN INACTIVATION OF TNF-ALPHA

Infection by Mycobacterium tuberculosis (MTB) induces human alveolar m acrophage (AM phi) apoptosis by a TNF-alpha-dependent mechanism. The a poptotic response is postulated to be a defense mechanism, limiting th e growth of this intracellular pathogen, Consistent with that model, r ecent studies showed that the virulent MTB strain H37Rv induces substa ntially less AM phi, apoptosis than the attenuated strain H37Ra, We no w report that AM phi infection with either H37Rv or H37Ra induces comp arable levels of TNF-alpha measured by ELISA but that TNF-alpha bioact ivity is reduced in supernatants of H37Rv-infected AM phi. Differentia l release of soluble TNFR2 (sTNFR2), with formation of inactive TNF-al pha-TNFR2 complexes accounted for the difference in TNF-alpha bioactiv ity in these cultures. Release of sTNFR2 by H37Rv-infected AM phi was IL-10 dependent since it was inhibited by neutralizing anti-IL-10 Ab, Thus, the effect of TNF-alpha produced by AM phi following infection c an be modulated by virulent MTB, using IL-10 as an upstream mediator.