Mycobacterium tuberculosis and Mycobacterium avium Inhibit IFN- γ -Induced Gene Expression by TLR2-Dependent and Independent Pathways

Mycobacteria-infected macrophages are poor responders to interferon-γ (IFN-γ), resulting in decreased expression of IFN-γ-induced genes. In the present study, we examined the inhibition of IFN-γ-induced gene expression by Mycobacterium tuberculosis and four different Mycobacterium avium strains in mouse RAW264.7 macrophages. Gamma-irradiated M. tuberculosis inhibited mRNA expression of a panel of six different IFN-γ-induced genes. All four of the M. avium strains completely inhibited IFN-γ-induced expression of MHC class II Aα and Eβ mRNA. However, the Mac101 strain, which is serovar 1, inhibited IFN-γ induction of IFN regulatory factor-1 (IRF-1) and guanylate-binding protein-1 (GBP-1) mRNA to a greater extent than the otherM. avium strains, which are serovar 2. In this study, we also show that mycobacteria inhibit gene expression by both toll-like receptor 2 (TLR2)-dependent and independent pathways. The inhibition of IFN-γ-induced gene expression by M. avium was reduced but not completely blocked in macrophages from TLR2^–/– mice. IFN-γ-induced gene expression was also inhibited by mycobacteria in RAW264.7 cells expressing dominantnegative TLR2 or myeloid differentiation factor 88 (MyD88), further indicating the existence of a pathway independent of TLR2 and MyD88. These data suggest that mycobacteria inhibit IFN-γ-induced gene expression by multiple pathways involving both TLR2 and non-TLR receptors.