Altered monocyte cyclo-oxygenase response in non-obese diabetic mice.
Monocytes infiltrate islets in non-obese diabetic (NOD) mice. Activated monocyte/macrophages express cyclo-oxygenase-2 (COX-2) promoting prostaglandin-E(2) (PGE(2)) secretion, while COX-1 expression is constitutive. We investigated in female NOD mice: (i) natural history of monocyte COX expression basally and following lipopolysaccharide (LPS) stimulation; (ii) impact of COX-2 specific inhibitor (Vioxx) on PGE(2), insulitis and diabetes. CD11b(+) monocytes were analysed for COX mRNA expression from NOD (n = 48) and C57BL/6 control (n = 18) mice. NOD mice were treated with either Vioxx (total dose 80 mg/kg) (n = 29) or methylcellulose as control (n = 29) administered by gavage at 4 weeks until diabetes developed or age 30 weeks. In all groups, basal monocyte COX mRNA and PGE(2) secretion were normal, while following LPS, after 5 weeks of age monocyte/macrophage COX-1 mRNA decreased (P < 0.01) and COX-2 mRNA increased (P < 0.01). However, diabetic NOD mice had reduced COX mRNA response (P = 0.03). Vioxx administration influenced neither PGE(2), insulitis nor diabetes. We demonstrate an isoform switch in monocyte/macrophage COX mRNA expression following LPS, which is altered in diabetic NOD mice as in human diabetes. However, Vioxx failed to affect insulitis or diabetes. We conclude that monocyte responses are altered in diabetic NOD mice but COX-2 expression is unlikely to be critical to disease risk.
Beyan
H
H
Centre for Diabetes and Metabolic Medicine (DMM), Institute of Cell and Molecular Science, London, UK. h.beyan@qmul.ac.uk
Buckley
L R
LR
Bustin
S A
SA
Yousaf
N
N
Pozzilli
P
P
Leslie
R D
RD
D000818:Animals; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007783:Lactones / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009000:Monocytes / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013450:Sulfones / Q000627:therapeutic use; D015854:Up-Regulation
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D013450:Sulfones; C116926:rofecoxib; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse