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

S. A. Litherland, X. T. Xie, A. D. Hutson, C. Wasserfall, D. S. Whittaker, Jin-Xiong She, A. Hofig, M. A. Dennis, K. Fuller, R. Cook, D. Schatz, L. L. Moldawer, M. J. Clare-Salzler

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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 α- 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 DQβ0302 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.

Original languageEnglish (US)
Pages (from-to)515-523
Number of pages9
JournalJournal of Clinical Investigation
Volume104
Issue number4
DOIs
StatePublished - Jan 1 1999

Fingerprint

Antigen-Presenting Cells
Prostaglandin-Endoperoxide Synthases
Type 1 Diabetes Mellitus
Monocytes
Autoantibodies
Prostaglandins
T-Lymphocytes
Interleukin-2 Receptors
Histocompatibility Antigens Class II
Phytohemagglutinins
Alleles
Macrophages
Insulin
Inflammation
Lipids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Aberrant prostaglandin synthase 2 expression defines an antigen- presenting cell defect for insulin-dependent diabetes mellitus. / Litherland, S. A.; Xie, X. T.; Hutson, A. D.; Wasserfall, C.; Whittaker, D. S.; She, Jin-Xiong; Hofig, A.; Dennis, M. A.; Fuller, K.; Cook, R.; Schatz, D.; Moldawer, L. L.; Clare-Salzler, M. J.

In: Journal of Clinical Investigation, Vol. 104, No. 4, 01.01.1999, p. 515-523.

Research output: Contribution to journalArticle

Litherland, SA, Xie, XT, Hutson, AD, Wasserfall, C, Whittaker, DS, She, J-X, Hofig, A, Dennis, MA, Fuller, K, Cook, R, Schatz, D, Moldawer, LL & Clare-Salzler, MJ 1999, 'Aberrant prostaglandin synthase 2 expression defines an antigen- presenting cell defect for insulin-dependent diabetes mellitus', Journal of Clinical Investigation, vol. 104, no. 4, pp. 515-523. https://doi.org/10.1172/JCI4852
Litherland, S. A. ; Xie, X. T. ; Hutson, A. D. ; Wasserfall, C. ; Whittaker, D. S. ; She, Jin-Xiong ; Hofig, A. ; Dennis, M. A. ; Fuller, K. ; Cook, R. ; Schatz, D. ; Moldawer, L. L. ; Clare-Salzler, M. J. / Aberrant prostaglandin synthase 2 expression defines an antigen- presenting cell defect for insulin-dependent diabetes mellitus. In: Journal of Clinical Investigation. 1999 ; Vol. 104, No. 4. pp. 515-523.
@article{3c153564a9c0416297dcbd93655fe21b,
title = "Aberrant prostaglandin synthase 2 expression defines an antigen- presenting cell defect for insulin-dependent diabetes mellitus",
abstract = "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 α- 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 DQβ0302 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.",
author = "Litherland, {S. A.} and Xie, {X. T.} and Hutson, {A. D.} and C. Wasserfall and Whittaker, {D. S.} and Jin-Xiong She and A. Hofig and Dennis, {M. A.} and K. Fuller and R. Cook and D. Schatz and Moldawer, {L. L.} and Clare-Salzler, {M. J.}",
year = "1999",
month = "1",
day = "1",
doi = "10.1172/JCI4852",
language = "English (US)",
volume = "104",
pages = "515--523",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - Aberrant prostaglandin synthase 2 expression defines an antigen- presenting cell defect for insulin-dependent diabetes mellitus

AU - Litherland, S. A.

AU - Xie, X. T.

AU - Hutson, A. D.

AU - Wasserfall, C.

AU - Whittaker, D. S.

AU - She, Jin-Xiong

AU - Hofig, A.

AU - Dennis, M. A.

AU - Fuller, K.

AU - Cook, R.

AU - Schatz, D.

AU - Moldawer, L. L.

AU - Clare-Salzler, M. J.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - 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 α- 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 DQβ0302 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.

AB - 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 α- 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 DQβ0302 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.

UR - http://www.scopus.com/inward/record.url?scp=0032694583&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032694583&partnerID=8YFLogxK

U2 - 10.1172/JCI4852

DO - 10.1172/JCI4852

M3 - Article

VL - 104

SP - 515

EP - 523

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -