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

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/ß. 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/ß. 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/ß receptor pathway. As IFN-γ and IFN-α have been implicated in the development of autoimmunity towards ß-cells, such an unanticipated selectivity in IFN responsiveness may provide a new insight into the pathogenesis of T1D.