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 macrophage (AMphi) apoptosis by a TNF-alpha-dependent mechanism. The apoptotic response is postulated to be a defense mechanism, limiting the growth of this intracellular pathogen. Consistent with that model, recent studies showed that the virulent MTB strain H37Rv induces substantially less AMphi apoptosis than the attenuated strain H37Ra. We now report that AMphi infection with either H37Rv or H37Ra induces comparable levels of TNF-alpha measured by ELISA but that TNF-alpha bioactivity is reduced in supernatants of H37Rv-infected AMphi. Differential release of soluble TNFR2 (sTNFR2), with formation of inactive TNF-alpha-TNFR2 complexes accounted for the difference in TNF-alpha bioactivity in these cultures. Release of sTNFR2 by H37Rv-infected AMphi was IL-10 dependent since it was inhibited by neutralizing anti-IL-10 Ab. Thus, the effect of TNF-alpha produced by AMphi following infection can be modulated by virulent MTB, using IL-10 as an upstream mediator.
Balcewicz-Sablinska
M K
MK
Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Keane
J
J
Kornfeld
H
H
Remold
H G
HG
D015703:Antigens, CD / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014774:Virulence
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10