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Diabetes 55:3439-3445, 2006
DOI: 10.2337/db06-0447
© 2006 by the American Diabetes Association
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Altered Monocyte Cyclooxygenase Response to Lipopolysaccharide in Type 1 Diabetes

Huriya Beyan1, Martin R. Goodier2, Niga S. Nawroly2, Mohammed I. Hawa1, Stephen A. Bustin3, William B. Ogunkolade3, Marco Londei2, Nasim Yousaf1, and R. David G. Leslie1

1 Centre for Diabetes and Metabolic Medicine (DMM), Institute of Cell and Molecular Science, London, U.K
2 Surgery Unit, Institute of Child Health, London, U.K
3 Centre for Academic Surgery, Institute of Cell and Molecular Science, Barts and The London, London, U.K

Address correspondence and reprint requests to Prof. David Leslie, Department of Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, London E1 2AT, U.K. E-mail: r.d.g.leslie{at}qmul.ac.uk

Abbreviations: BCIP, 5-bromo-4-chloro-3'-indolyphosphate p-toluidine salt; COX, cyclooxygenase; DFP, di-isopropylfluorophosphate; FACS, fluorescence-activated cell sorting; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; LPS, lipopolysaccharide; NBT, nitro-blue tetrazolium chloride; PBMC, peripheral blood mononuclear cell; PG, prostaglandin

Type 1 diabetes is caused by adaptive immune responses, but innate immunity is important because monocytes infiltrate islets. Activated monocytes express cyclooxygenase (COX)-2, promoting prostaglandin-E2 (PGE2) secretion, whereas COX-1 expression is constitutive. We aimed to define monocyte COX expression in type 1 diabetes basally and after lipopolysaccharide (LPS) stimulation. Isolated CD14+ monocytes were analyzed for COX mRNA and protein expression from identical twins (discordant for type 1 diabetes) and control subjects. Basal monocyte COX mRNA, protein expression, and PGE2 secretion were normal in type 1 diabetic subjects. After LPS, twins and control subjects showed a COX mRNA isoform switch with decreased COX-1 mRNA (P < 0.01), increased COX-2 mRNA (P < 0.01), and increased COX-2 protein expression (P < 0.01). Compared with control subjects, both diabetic and nondiabetic twins showed greater LPS-induced downregulation of monocyte COX-1 mRNA (P = 0.02), reduced upregulation of COX-2 mRNA and protein (P < 0.03), and greater inhibition by the COX-2 inhibitor di-isopropylfluorophosphate (DFP) of monocyte PGE2 (P < 0.007). We demonstrate an alteration in monocyte COX mRNA expression as well as monocyte COX-2 and PGE2 production after LPS in type 1 diabetic patients and their nondiabetic twins. Because COX-2 response to LPS is proinflammatory, an inherited reduced response would predispose to chronic inflammatory diseases such as type 1 diabetes.


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Copyright © 2006 by the American Diabetes Association.