Macrophages from nonobese diabetic mouse have a selective defect in IFN-γ but not IFN-α/β receptor pathway

J Clin Immunol. 2012 Aug;32(4):753-61. doi: 10.1007/s10875-012-9682-3. Epub 2012 Mar 7.

Abstract

Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • Interferon gamma Receptor
  • Interferon-alpha / immunology*
  • Interferon-alpha / metabolism
  • Interferon-beta / immunology
  • Interferon-beta / metabolism
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Janus Kinase 2 / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Phosphorylation
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism*
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interferon-alpha
  • Lipopolysaccharides
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Receptor, Interferon alpha-beta
  • Interleukin-12
  • Interferon-beta
  • Interferon-gamma
  • Jak2 protein, mouse
  • Janus Kinase 2