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Divisions of
*
Rheumatology and
Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109; and
Division of Chemistry II, Karolinska Institutet, MBB, Stockholm, Sweden
The selective induction of PGE2 synthesis in
inflammation suggests that a PGE synthase may be linked to an inducible
pathway for PG synthesis. We examined the expression of the recently
cloned inducible microsomal PGE synthase (mPGES) in synoviocytes from
patients with rheumatoid arthritis, its modulation by cytokines and
dexamethasone, and its linkage to the inducible cyclooxygenase-2.
Northern blot analysis showed that IL-1
or TNF-
treatment induces
mPGES mRNA from very low levels at baseline to maximum levels at
24 h. IL-1-induced mPGES mRNA was inhibited by dexamethasone in
a dose-dependent fashion. Western blot analysis demonstrated that mPGES
protein was induced by IL-1, and maximum expression was sustained
for up to 72 h. There was a coordinated up-regulation of
cyclooxygenase-2 protein, although peak expression was earlier.
Differential Western blot analysis of the microsomal and the cytosolic
fractions revealed that the induced expression of mPGES protein was
limited to the microsomal fraction. The detected mPGES protein was
catalytically functional as indicated by a 3-fold increase of PGES
activity in synoviocytes following treatment with IL-1; this
increased synthase activity was limited to the microsomal fraction. In
summary, these data demonstrate an induction of mPGES in rheumatoid
synoviocytes by proinflammatory cytokines. This novel pathway may be a
target for therapeutic intervention for patients with
arthritis.
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C. E. Trebino, J. L. Stock, C. P. Gibbons, B. M. Naiman, T. S. Wachtmann, J. P. Umland, K. Pandher, J.-M. Lapointe, S. Saha, M. L. Roach, et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase PNAS, July 22, 2003; 100(15): 9044 - 9049. [Abstract] [Full Text] [PDF]
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S. Thoren, R. Weinander, S. Saha, C. Jegerschold, P. L. Pettersson, B. Samuelsson, H. Hebert, M. Hamberg, R. Morgenstern, and P.-J. Jakobsson Human Microsomal Prostaglandin E Synthase-1: PURIFICATION, FUNCTIONAL CHARACTERIZATION, AND PROJECTION STRUCTURE DETERMINATION J. Biol. Chem., June 13, 2003; 278(25): 22199 - 22209. [Abstract] [Full Text] [PDF]
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R. Han and T. J. Smith Cytoplasmic Prostaglandin E2 Synthase Is Dominantly Expressed in Cultured KAT-50 Thyrocytes, Cells That Express Constitutive Prostaglandin-endoperoxide H Synthase-2. BASIS FOR LOW PROSTAGLANDIN E2 PRODUCTION J. Biol. Chem., September 20, 2002; 277(39): 36897 - 36903. [Abstract] [Full Text] [PDF]
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H. Naraba, C. Yokoyama, N. Tago, M. Murakami, I. Kudo, M. Fueki, S. Oh-ishi, and T. Tanabe Transcriptional Regulation of the Membrane-associated Prostaglandin E2 Synthase Gene. ESSENTIAL ROLE OF THE TRANSCRIPTION FACTOR Egr-1 J. Biol. Chem., August 2, 2002; 277(32): 28601 - 28608. [Abstract] [Full Text] [PDF]
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