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
| Autor: | Christina L. Sherry, Gregory G. Freund, Jason C. O'Connor, Christopher B. Guest |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
medicine.medical_treatment Molecular Sequence Data Immunology Mice Transgenic Suppressor of Cytokine Signaling Proteins Biology Cell Line Proinflammatory cytokine Wortmannin Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Internal medicine medicine Animals Immunology and Allergy Amino Acid Sequence SOCS3 Kinase activity Interleukin 4 Phosphoinositide-3 Kinase Inhibitors Intracellular Signaling Peptides and Proteins Tyrosine phosphorylation Phosphoproteins Molecular biology Receptor Insulin IRS2 Mice Inbred C57BL Endocrinology Cytokine Diabetes Mellitus Type 2 chemistry Suppressor of Cytokine Signaling 3 Protein Insulin Receptor Substrate Proteins Macrophages Peritoneal Cytokines Interleukin-4 Signal Transduction |
| Zdroj: | The Journal of Immunology. 178:6886-6893 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.178.11.6886 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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