title: Macrophages from nonobese diabetic mouse have a selective defect in IFN-γ but not IFN-α/β receptor pathway.
abstract: OBJECTIVE
  Aberrant regulation of innate immune cells such as macrophages has been implicated in the onset and progression of type 1 diabetes (T1D). Macrophages from nonobese diabetic (NOD) mouse, an animal model of T1D, entail developmental and functional defects that are often associated with hypo-responsiveness to interferon (IFN)-γ. We aimed to uncover a mechanism underlying this phenomenon.
  
  
  METHODS
  We analyzed the receptor pathway along with the response of macrophages exposed to IFN-γ and the related IFNs such as IFN-α/β.
  
  
  RESULTS
  We found that NOD macrophages failed to fully respond to IFN-γ but not to IFN-α for the production of inflammatory cytokines (e.g. TNF-α and IL-12). NOD macrophages were also resistant to apoptotic pathway induced by IFN-γ and LPS. Analyses of receptor pathway revealed that STAT1 pathway of intracellular signaling was selectively impaired in NOD macrophages exposed to IFN-γ but not to IFN-α/β. Further, these defects correlated with a low phosphorylation level of JAK2, and were related to impaired up-regulation of surface IFN-γ receptor 2 (IFN-γR2) by IFN-γ.
  
  
  CONCLUSIONS
  Taken together, our results suggest that NOD macrophages have a selective defect in IFN-γ but not IFN-α/β receptor pathway. As IFN-γ and IFN-α have been implicated in the development of autoimmunity towards β-cells, such an unanticipated selectivity in IFN responsiveness may provide a new insight into the pathogenesis of T1D.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Hyung-Joon
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Hun Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D018664:Interleukin-12; D053614:Janus Kinase 2; D008070:Lipopolysaccharides; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse; C507926:Jak2 protein, mouse