Macrophages from Nonobese Diabetic Mouse Have a Selective Defect in IFN-gamma but Not IFN-alpha/beta Receptor Pathway

作者：Lee Myung Shik; Kwon Hyung Joon; Kim Hun Sik^*

来源：Journal of Clinical Immunology, 2012, 32(4): 753-761.

DOI：10.1007/s10875-012-9682-3

• Autoimmune diabetes
• macrophage
• IFN-gamma
• IFN-alpha/beta
• STAT1
• IFN-gamma R2

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)-gamma. We aimed to uncover a mechanism underlying this phenomenon. %26lt;br%26gt;We analyzed the receptor pathway along with the response of macrophages exposed to IFN-gamma and the related IFNs such as IFN-alpha/beta. %26lt;br%26gt;We found that NOD macrophages failed to fully respond to IFN-gamma but not to IFN-alpha for the production of inflammatory cytokines (e.g. TNF-alpha and IL-12). NOD macrophages were also resistant to apoptotic pathway induced by IFN-gamma and LPS. Analyses of receptor pathway revealed that STAT1 pathway of intracellular signaling was selectively impaired in NOD macrophages exposed to IFN-gamma but not to IFN-alpha/beta. Further, these defects correlated with a low phosphorylation level of JAK2, and were related to impaired up-regulation of surface IFN-gamma receptor 2 (IFN-gamma R2) by IFN-gamma. %26lt;br%26gt;Taken together, our results suggest that NOD macrophages have a selective defect in IFN-gamma but not IFN-alpha/beta receptor pathway. As IFN-gamma and IFN-alpha have been implicated in the development of autoimmunity towards beta-cells, such an unanticipated selectivity in IFN responsiveness may provide a new insight into the pathogenesis of T1D.

• 出版日期2012-8