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Type 2 Diabetes Impairs Insulin Receptor Substrate-2-Mediated Phosphatidylinositol 3-Kinase Activity in Primary Macrophages to Induce a State of Cytokine Resistance to IL-4 in Association with Overexpression of Suppressor of Cytokine Signaling-3¹

Jason C. O’Connor^*, Christina L. Sherry^*, Christopher B. Guest^* and Gregory G. Freund^2,*,

^* Division of Nutritional Sciences, and Department of Pathology, Integrative Immunology and Behavior Program, University of Illinois, Urbana, IL 61801

Chronic elevation of proinflammatory markers in type 2 diabetes (T2D) is well defined, but the role of anti-inflammatory cytokines in T2D is less clear. In this study, we report that normal IL-4-dependent elaboration of IL-1 receptor antagonist (IL-1RA) requires IRS-2-mediated PI3K activity in primary macrophages. We also show that macrophages isolated from obese/diabetic db/db mice have impaired IRS-2-mediated PI3K activity and constitutively overexpress suppressor of cytokine signaling (SOCS)-3, which impairs an important IL-4 anti-inflammatory function. Peritoneal proinflammatory cytokine levels were examined in diabese (db/db) mice, and IL-6 was found to be nearly 7-fold higher than in nondiabese (db/+) control mice. Resident peritoneal macrophages were isolated from db/db mice and were found to constitutively overexpress IL-6 and were unable to elaborate IL-1RA in response to IL-4-like db/+ mouse macrophages. Inhibition of PI3K with wortmannin or blockage of IRS-2/PI3K complex formation with a cell permeable IRS-2-derived tyrosine phosphopeptide inhibited IL-4-dependent IL-1RA production in db/+ macrophages. Examination of IL-4 signaling in db/db macrophages revealed that IL-4-dependent IRS-2/PI3K complex formation and IRS-2 tyrosine phosphorylation was reduced compared with db/+ macrophages. SOCS-3/IL-4 receptor complexes, however, were increased in db/db mouse macrophages compared with db/+ mice macrophages as was db/db mouse macrophage SOCS-3 expression. These results indicate that in the db/db mouse model of T2D, macrophage expression of SOCS-3 is increased, and impaired IL-4-dependent IRS-2/PI3K formation induces a state of IL-4 resistance that disrupts IL-4-dependent production of IL-1RA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by grants from the National Institutes of Health (DK064862 to G.G.F. and Postdoctoral Fellowship DK59802 to J.C.O.), American Heart Association (Established Investigator Award to G.G.F. and Predoctoral Fellowship to J.C.O.), University of Illinois Agricultural Experiment Station (to G.G.F.), and Predoctoral Fellowship DK59802 (to C.B.G.).

² Address correspondence and reprint requests to Dr. Gregory G. Freund, Department of Pathology, College of Medicine, 506 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, IL 61801. E-mail address: freun{at}uiuc.edu

³ Abbreviations used in this paper: T2D, type 2 diabetes; IGF-1, insulin-like growth factor-1; IRS, insulin receptor substrate; IL-1RA, IL-1 receptor antagonist; IL-1R2, type-2 IL-1 receptor; SH, Src homology; SOCS, suppressor of cytokine signaling.

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