Altered monocyte cyclooxygenase response to lipopolysaccharide in type 1 diabetes.
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-E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) (P < 0.007). We demonstrate an alteration in monocyte COX mRNA expression as well as monocyte COX-2 and PGE(2) 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.
Beyan
Huriya
H
Department of Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, London E1 2AT, U.K.
Goodier
Martin R
MR
Nawroly
Niga S
NS
Hawa
Mohammed I
MI
Bustin
Stephen A
SA
Ogunkolade
William B
WB
Londei
Marco
M
Yousaf
Nasim
N
Leslie
R David G
RD
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000097:blood / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000097:blood / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2