Mycobacteria-induced granuloma necrosis depends on IRF-1

J Cell Mol Med. 2009 Aug;13(8B):2069-2082. doi: 10.1111/j.1582-4934.2008.00470.x. Epub 2008 Aug 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Granuloma / microbiology*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / physiology*
  • Interleukin-18 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium avium / pathogenicity*
  • Necrosis
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DNA Primers
  • Interferon Regulatory Factor-1
  • Interleukin-18