title: Mycobacterium tuberculosis and Mycobacterium avium inhibit IFN- gamma -induced gene expression by TLR2-dependent and independent pathways.
abstract: Mycobacteria-infected macrophages are poor responders to interferon-gamma (IFN-gamma), resulting in decreased expression of IFN-gamma-induced genes. In the present study, we examined the inhibition of IFN-gamma-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- gamma-induced genes. All four of the M. avium strains completely inhibited IFN-gamma-induced expression of MHC class II Aalpha and Ebeta mRNA. However, the Mac101 strain, which is serovar 1, inhibited IFN-gamma induction of IFN regulatory factor-1 (IRF-1) and guanylate-binding protein-1 (GBP-1) mRNA to a greater extent than the other M. 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-gamma-induced gene expression by M. avium was reduced but not completely blocked in macrophages from TLR2(/) mice. IFN-gamma-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-gamma-induced gene expression by multiple pathways involving both TLR2 and non-TLR receptors.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA. lafuse.1@osu.edu
authors.forename: William P
authors.initials: WP
authors.lastname: Lafuse
authors.forename: Gail R
authors.initials: GR
authors.lastname: Alvarez
authors.forename: Heather M
authors.initials: HM
authors.lastname: Curry
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Zwilling
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009162:Mycobacterium avium / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D007371:Interferon-gamma