Aberrant prostaglandin synthase 2 expression defines an antigen-presentingcell defect for insulin-dependent diabetes mellitus

Prostaglandins (PGs) are lipid molecules that profoundly affect cellular pr ocesses including inflammation and immune response. Pathways contributing t o PG output are highly regulated in antigen-presenting cells such as macrop hages and monocytes, which produce large quantities of these molecules upon activation. In this report, we demonstrate aberrant constitutive expressio n of the normally inducible cyclooxygenase PG synthase 2 (PGS(2)/ COX-2) in nonactivated monocytes of humans with insulin-dependent diabetes mellitus (IDDM) and those with islet autoantibodies at increased risk of developing this disease. Constitutive PGS(2) appears to characterize a high risk for d iabetes as it correlates with and predicts a low first-phase insulin respon se in autoantibody-positive subjects. Abnormal PGS(2) expression in at-risk subjects affected immune response in vitro, as the presence of a specific PGS(2) inhibitor, NS398, significantly increased IL-2 receptor alpha-chain (CD25) expression on phytohemagglutinin-stimulated T cells. The effect of P GS(2) on CD25 expression was most profound in subjects expressing both DR04 and DQP0302 high-risk alleles, suggesting that this cyclooxygenase interac ts with diabetes-associated MHC class II antigens to limit T-cell activatio n. These results indicate that constitutive PGS(2) expression in monocytes defines an antigen-presenting cell defect affecting immune response, and th at this expression is a novel cell-associated risk marker for IDDM.