Mycobacteria-induced granuloma necrosis depends on IRF-1.
In a mouse model of mycobacteria-induced immunopathology, wild-type C57BL/6 (WT), IL-18-knockout (KO) and IFN-alphabeta receptor-KO mice developed circumscript, centrally necrotizing granulomatous lesions in response to aerosol infection with M. avium, whereas mice deficient in the IFN-gamma receptor, STAT-1 or IRF-1 did not exhibit granuloma necrosis. Comparative, microarray-based gene expression analysis in the lungs of infected WT and IRF-1-KO mice identified a set of genes whose differential regulation was closely associated with granuloma necrosis, among them cathepsin K, cystatin F and matrix metalloprotease 10. Further microarray-based comparison of gene expression in the lungs of infected WT, IFN-gamma-KO and IRF-1-KO mice revealed four distinct clusters of genes with variable dependence on the presence of IFN-gamma, IRF-1 or both. In particular, IRF-1 appeared to be directly involved in the differentiation of a type I immune response to mycobacterial infection. In summary, IRF-1, rather than being a mere transcription factor downstream of IFN-gamma, may be a master regulator of mycobacteria-induced immunopathology.
Aly
Sahar
S
Molecular Infection Biology, Research Center Borstel, Borstel, Germany.
Mages
Jörg
J
Medical Microbiology, Immunology and Hygiene, Technical University of Munich, München, Germany.
Reiling
Norbert
N
Molecular Infection Biology, Research Center Borstel, Borstel, Germany.
Kalinke
Ulrich
U
Immunology, Paul-Ehrlich-Institut, Langen, Germany.
Decker
Thomas
T
Microbiology and Immunobiology, University of Vienna, Wien, Austria.
Lang
Roland
R
Medical Microbiology, Immunology and Hygiene, Technical University of Munich, München, Germany.
Ehlers
Stefan
S
Molecular Infection Biology, Research Center Borstel, Borstel, Germany.|Molecular Inflammation Medicine, Christian-Albrechts - University Kiel, Kiel, Germany.
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006099:Granuloma / Q000382:microbiology*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009162:Mycobacterium avium / Q000472:pathogenicity*; D009336:Necrosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D050856:Interferon Regulatory Factor-1; D020382:Interleukin-18