Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus.
Prostaglandins (PGs) are lipid molecules that profoundly affect cellular processes including inflammation and immune response. Pathways contributing to PG output are highly regulated in antigen-presenting cells such as macrophages and monocytes, which produce large quantities of these molecules upon activation. In this report, we demonstrate aberrant constitutive expression 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 diabetes as it correlates with and predicts a low first-phase insulin response 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 PGS(2) on CD25 expression was most profound in subjects expressing both DR04 and DQbeta0302 high-risk alleles, suggesting that this cyclooxygenase interacts with diabetes-associated MHC class II antigens to limit T-cell activation. These results indicate that constitutive PGS(2) expression in monocytes defines an antigen-presenting cell defect affecting immune response, and that this expression is a novel cell-associated risk marker for IDDM.
Litherland
S A
SA
Department of Immunology, Pathology, and Laboratory Medicine, College of Medicine, College of Medicine, University of Florida, Gainesville 32610, USA.
Xie
X T
XT
Hutson
A D
AD
Wasserfall
C
C
Whittaker
D S
DS
She
J X
JX
Hofig
A
A
Dennis
M A
MA
Fuller
K
K
Cook
R
R
Schatz
D
D
Moldawer
L L
LL
Clare-Salzler
M J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000938:Antigen-Presenting Cells / Q000201:enzymology*; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D005260:Female; D005802:Genes, MHC Class II; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012307:Risk Factors; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
D001323:Autoantibodies; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D015375:Receptors, Interleukin-2; D013449:Sulfonamides; C024211:islet cell antibody; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases