title: 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-3.
abstract: 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.
authors.affiliation: Division of Nutritional Sciences, Integrative Immunology and Behavior Program, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: O'Connor
authors.forename: Christina L
authors.initials: CL
authors.lastname: Sherry
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Guest
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Freund
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology
chemical_list: D016207:Cytokines; D055504:Insulin Receptor Substrate Proteins; D015847:Interleukin-4; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011972:Receptor, Insulin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C526298:Irs2 protein, mouse; C491411:Socs3 protein, mouse