Induction of macrophage-derived SLPI by Mycobacterium tuberculosis depends on TLR2 but not MyD88.
Macrophages respond to Mycobacterium tuberculosis by regulating expression of gene products that initiate a host innate response to this micro-organism. In this study, we report that exposure of murine peritoneal macrophages to heat-killed Mycobacterium tuberculosis (HK-Mtb) led to an increase in secretory leucocyte protease inhibitor (SLPI) gene expression and protein secretion in a time- and dose-dependent manner. HK-Mtb-induced SLPI mRNA expression was sensitive neither to a protein synthesis inhibitor, cycloheximide, nor to an actin polymerization blocker, cytochalasin D. Treatment of macrophages with interferon (IFN)-gamma inhibited HK-Mtb-induced SLPI expression. RAW264.7 cells stably expressing SLPI produced a reduced level of tumour necrosis factor (TNF) in response to HK-Mtb as compared with mock transfectants. Aerosol infection of mice with live M. tuberculosis resulted in an induction of SLPI gene expression in infected lungs. Macrophages from Toll-like receptor 4 (TLR4)-/- or MyD88-/- mice responded to M. tuberculosis similarly to wild-type macrophages by exhibiting increased SLPI expression. In contrast, macrophages from TLR2-/- mice were incapable of inducing SLPI in response to M. tuberculosis. This induction signifies the presence of a TLR2-dependent but MyD88-independent M. tuberculosis signalling pathway, suggesting involvement of adaptor protein(s) other than MyD88 in M. tuberculosis-mediated induction of SLPI.
Ding
Aihao
A
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA. ahding@med.cornell.edu
Yu
Hongwei
H
Yang
Jingxuan
J
Shi
Shuangping
S
Ehrt
Sabine
S
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D015152:Blotting, Northern; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D053481:Secretory Leukocyte Peptidase Inhibitor; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D000943:Antigens, Differentiation; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011971:Receptors, Immunologic; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma