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J Biol Chem, Vol. 273, Issue 45, 29615-29625, November 6, 1998
From the Human orbital fibroblasts play a
putative role in the pathogenesis of thyroid-associated ophthalmopathy
(TAO). We hypothesize that the hyaluronan accumulation and inflammation
in TAO derive from enhanced biosynthetic activities of orbital
fibroblasts. CD40, a member of the tumor necrosis factor-
Activation of Human Orbital Fibroblasts through CD40 Engagement
Results in a Dramatic Induction of Hyaluronan Synthesis and
Prostaglandin Endoperoxide H Synthase-2 Expression
INSIGHTS INTO POTENTIAL PATHOGENIC MECHANISMS OF
THYROID-ASSOCIATED OPHTHALMOPATHY
§,
,,, and§
Division of Molecular and Cellular Medicine, University of Rochester
Cancer Center and Departments of Microbiology and Immunology,
Pediatrics and Environmental Medicine, Rochester, New York 14642
receptor
superfamily, is a critical signaling molecule expressed by B
lymphocytes. Engagement of CD40 with CD154 or CD40 ligand results in
the activation of target genes. Orbital fibroblasts also display CD40.
Here we report that CD40 engagement leads to substantial increases in
hyaluronan synthesis in orbital fibroblasts. The increase is
approximately 5-fold above control values, is comparable to the
induction elicited by IL-1
and could be attenuated with
dexamethasone but not by SC 58125, a prostaglandin endoperoxide H
synthase-2 (PGHS-2)-selective inhibitor. PGHS-2 is also induced by CD40
engagement in a time-dependent manner, and this is mediated
through increases in levels of steady-state mRNA. The induction of
PGHS-2 leads to a dramatically enhanced prostaglandin
E2 production that can be blocked by SC 58125 and dexamethasone. CD40 ligand up-regulates the synthesis of IL-1, and
blocking this cytokine with exogenous IL-1 receptor antagonist (IL-1ra)
or with IL-1 neutralizing antibodies partially attenuates the
induction of PGHS-2. In contrast, CD40 ligand up-regulation of
hyaluronan synthesis is unaffected by IL-1ra. CD40 cross-linking enhances mitogen-activated protein kinase activation, and interrupting this pathway attenuates the PGHS-2 induction. Thus the CD40/CD40 ligand
bridge represents a potentially important activational pathway for
orbital fibroblasts that may underlie the cross-talk between these
cells and leukocytes. These findings may be relevant to the
pathogenesis of TAO and provide insights into previously unrecognized, potential therapeutic targets.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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R. F. Schwabe, B. Schnabl, Y. O. Kweon, and D. A. Brenner CD40 Activates NF-{{kappa}}B and c-Jun N-Terminal Kinase and Enhances Chemokine Secretion on Activated Human Hepatic Stellate Cells J. Immunol., June 1, 2001; 166(11): 6812 - 6819. [Abstract] [Full Text] [PDF]
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A. G. Gianoukakis, H. J. Cao, T. A. Jennings, and T. J. Smith Prostaglandin endoperoxide H synthase expression in human thyroid epithelial cells Am J Physiol Cell Physiol, March 1, 2001; 280(3): C701 - C708. [Abstract] [Full Text] [PDF]
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J. Padilla, K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps Peroxisome Proliferator Activator Receptor-{gamma} Agonists and 15-Deoxy-{Delta}12,1412,14-PGJ2 Induce Apoptosis in Normal and Malignant B-Lineage Cells J. Immunol., December 15, 2000; 165(12): 6941 - 6948. [Abstract] [Full Text] [PDF]
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A. Bell, A. Gagnon, L. Grunder, S. J. Parikh, T. J. Smith, and A. Sorisky Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts Am J Physiol Cell Physiol, August 1, 2000; 279(2): C335 - C340. [Abstract] [Full Text] [PDF]
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D. Sciaky, W. Brazer, D. M. Center, W. W. Cruikshank, and T. J. Smith Cultured Human Fibroblasts Express Constitutive IL-16 mRNA: Cytokine Induction of Active IL-16 Protein Synthesis Through a Caspase-3-Dependent Mechanism J. Immunol., April 1, 2000; 164(7): 3806 - 3814. [Abstract] [Full Text] [PDF]
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Y.-i. Hwang, M. H. Nahm, D. E. Briles, D. Thomas, and J. M. Purkerson Acquired, but Not Innate, Immune Responses to Streptococcus pneumoniae Are Compromised by Neutralization of CD40L Infect. Immun., February 1, 2000; 68(2): 511 - 517. [Abstract] [Full Text] [PDF]
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H. J. Cao and T. J. Smith Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression in human orbital fibroblasts Am J Physiol Cell Physiol, December 1, 1999; 277(6): C1075 - C1085. [Abstract] [Full Text] [PDF]
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L. A. Kaback and T. J. Smith Expression of Hyaluronan Synthase Messenger Ribonucleic Acids and Their Induction by Interleukin-1{beta} in Human Orbital Fibroblasts: Potential Insight into the Molecular Pathogenesis of Thyroid-Associated Ophthalmopathy J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4079 - 4084. [Abstract] [Full Text]
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T. J. Smith and S. J. Parikh HMC-1 Mast Cells Activate Human Orbital Fibroblasts in Coculture: Evidence for Up-Regulation of Prostaglandin E2 and Hyaluronan Synthesis Endocrinology, August 1, 1999; 140(8): 3518 - 3525. [Abstract] [Full Text]
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T. J. Smith, T. A. Jennings, D. Sciaky, and H. J. Cao Prostaglandin-endoperoxide H Synthase-2 Expression in Human Thyroid Epithelium. EVIDENCE FOR CONSTITUTIVE EXPRESSION IN VIVO AND IN CULTURED KAT-50 CELLS J. Biol. Chem., May 28, 1999; 274(22): 15622 - 15632. [Abstract] [Full Text] [PDF]
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