Abstract
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-alpha 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-1beta 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-1alpha, and blocking this cytokine with exogenous IL-1 receptor antagonist (IL-1ra) or with IL-1alpha 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.
Highlights
Human orbital fibroblasts play a putative role in the pathogenesis of thyroid-associated ophthalmopathy (TAO)
The Induction of prostaglandin endoperoxide H synthase-2 (PGHS-2) Expression but Not Hyaluronan Production Elicited by CD40 Engagement Is Dependent upon Intermediate IL-1␣ Production—Because we have found that IL-1 induces prostaglandin endoperoxide-H synthases (PGHS)-2 expression and hyaluronan synthesis in orbital fibroblasts, we examined the impact of neutralizing the action of the cytokine on PGE2 production and PGHS-2 expression elicited by CD40 ligand
Human orbital fibroblasts can be activated through the CD40/CD40 ligand bridge to express substantially greater levels of hyaluronan and PGE2, as the current studies have demonstrated
Summary
Vol 273, No 45, Issue of November 6, pp. 29615–29625, 1998 Printed in U.S.A. INSIGHTS INTO POTENTIAL PATHOGENIC MECHANISMS OF THYROID-ASSOCIATED OPHTHALMOPATHY*. We have found that orbital fibroblasts are susceptible to the up-regulation of PGHS-2 expression by certain pro-inflammatory cytokines such as leukoregulin, a 50-kDa product of activated T lymphocytes and IL-1 [31] This induction, mediated through both transcriptional and post-transcriptional mechanisms, results in dramatic increases in the production of PGE2. We have identified a previously unrecognized mechanism for the activation of orbital fibroblasts through the CD40/CD40 ligand bridge that can explain the participation of these fibroblasts in situ in the tissue remodeling observed in TAO This fibroblast-signaling pathway may represent a highly efficient and specific means by which the immune system can activate connective tissue cells in the setting of an inflammatory response. We hypothesize that the disruption of the CD40/CD40 ligand bridge, either directly or through the attenuation of the IL-1 autocrine loop, may represent an important therapeutic target relevant to TAO and other lymphocyte-driven forms of inflammation involving connective tissue
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