TLR2 but not TLR4 Signalling is Critically Involved in the Inhibition of IFN‐ γ ‐induced Killing of Mycobacteria by Murine Macrophages

Gamma‐interferon (IFN‐ γ ) 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‐ γ by blocking the transcription of a subset of IFN‐ γ inducible genes. This inhibition occurs after signalling through Toll‐like receptor 2 (TLR2). While most studies have investigated the inhibition of IFN‐ γ responsive genes after TLR2 signalling, the present study focuses on the functional implications of inhibition of IFN‐ γ 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‐ γ ‐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‐ γ ‐mediated killing. We demonstrate that 19‐kDa and zymosan inhibit the ability of IFN‐ γ 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‐ γ signalling is overcome with increasing amounts of IFN‐ γ indicating that the refractoriness could be reversed at optimal IFN‐ γ concentrations. The critical role of TLR2 but not TLR4 signalling in the inhibition of IFN‐ γ promoted killing of mycobacteria is discussed.