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Augmented Lipopolysaccharide-Induced TNF- Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK¹

Christina L. Sherry^*, Jason C. O’Connor^*, Jason M. Kramer and Gregory G. Freund^2,*,

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

Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF- production by resident peritoneal macrophages (PerM) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF- in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerM. Ex vivo stimulation of PerM with LPS produced a similar 3-fold increase in TNF- production in db/db PerM when compared with db/+ PerM. PerM isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF- in response to LPS than PerM incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerM from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF- production in PerM from db/db mice. Taken together, these data indicate that augmented TNF- production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.

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 work was supported by grants from the National Institutes of Health (DK64862 (to G.G.F.) and Postdoctoral Fellowship DK59802 (to J.C.O.)) and University of Illinois Agricultural Experiment Station (to G.G.F.).

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

³ Abbreviations used in this paper: T2D, type 2 diabetes; IRS, insulin receptor substrate; IL-1RA, IL-1R antagonist; PerM, peritoneal macrophage; pY, phosphotyrosine.

This article has been cited by other articles:

				J. C. O'Connor, C. L. Sherry, C. B. Guest, and G. G. Freund 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 J. Immunol., June 1, 2007; 178(11): 6886 - 6893. [Abstract] [Full Text] [PDF]