TLR2 but not TLR4 signalling is critically involved in the inhibition of IFN-gamma-induced killing of mycobacteria by murine macrophages.
Gamma-interferon (IFN-gamma) plays a determinant role in activating macrophages that are critical to control Mycobacterium tuberculosis infection. However, M. tuberculosis can escape killing by attenuating the response of macrophages to IFN-gamma by blocking the transcription of a subset of IFN-gamma inducible genes. This inhibition occurs after signalling through Toll-like receptor 2 (TLR2). While most studies have investigated the inhibition of IFN-gamma responsive genes after TLR2 signalling, the present study focuses on the functional implications of inhibition of IFN-gamma signalling in macrophages with regard to mycobacteria killing. Here, we provide evidence that exposure of the murine macrophage cell line J774 to the TLR2 ligands; 19-kDa or zymosan, but not the TLR4 ligand LPS, inhibits IFN-gamma-induced killing of Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Moreover, exposure of bone marrow-derived macrophages (BMM) from TLR4-deficient and wild-type (WT), but not from TLR2-deficient mice to 19-kDa lipoprotein (19-kDa) or zymosan, results in an impairment of IFN-gamma-mediated killing. We demonstrate that 19-kDa and zymosan inhibit the ability of IFN-gamma to activate murine macrophages to kill BCG without inhibiting nitric oxide (NO) or tumour necrosis factor (TNF) production. Finally, we demonstrate that the inhibitory effect of 19-kDa on IFN-gamma signalling is overcome with increasing amounts of IFN-gamma indicating that the refractoriness could be reversed at optimal IFN-gamma concentrations. The critical role of TLR2 but not TLR4 signalling in the inhibition of IFN-gamma promoted killing of mycobacteria is discussed.
Arko-Mensah
J
J
Immunology Department, Stockholm University, Stockholm, Sweden. john.arko-mensah@imun.su.se
Julián
E
E
Singh
M
M
Fernández
C
C
D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology*; D002460:Cell Line; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
C087864:19 kDa antigen, Mycobacterium; D001426:Bacterial Proteins; D008024:Ligands; D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D015054:Zymosan