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J. Biol. Chem., Vol. 282, Issue 21, 15416-15429, May 25, 2007

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Tissue-specific Mechanisms for CCN2/CTGF Persistence in Fibrotic Gingiva

INTERACTIONS BETWEEN cAMP AND MAPK SIGNALING PATHWAYS, AND PROSTAGLANDIN E₂-EP3 RECEPTOR MEDIATED ACTIVATION OF THE c-JUN N-TERMINAL KINASE^*

From the Department of Periodontology and Oral Biology, Division of Oral Biology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts 02118

Prostaglandin E₂ blocks transforming growth factor TGF 1-induced CCN2/CTGF expression in lung and kidney fibroblasts. PGE₂ levels are high in gingival tissues yet CCN2/CTGF expression is elevated in fibrotic gingival overgrowth. Gingival fibroblast expression of CCN2/CTGF in the presence of PGE₂ led us to compare the regulation of CCN2/CTGF expression in fibroblasts cultured from different tissues. Data demonstrate that the TGF1-induced expression of CCN2/CTGF in human lung and renal mesangial cells is inhibited by 10 nM PGE₂, whereas human gingival fibroblasts are resistant. Ten nM PGE₂ increases cAMP accumulation in lung but not gingival fibroblasts, which require 1 µM PGE₂ to elevate cAMP. Micromolar PGE₂ only slightly reduces the TGF1-stimulated CCN2/CTGF levels in gingival cells. EP2 prostaglandin receptor activation with butaprost blocks the TGF1-stimulated expression of CCN2/CTGF expression in lung, but not gingival, fibroblasts. In lung fibroblasts, inhibition of the TGF1-stimulated CCN2/CTGF by PGE₂, butaprost, or forskolin is due to p38, ERK, and JNK MAP kinase inhibition that is cAMP-dependent. Inhibition of any two MAPKs completely blocks CCN2/CTGF expression stimulated by TGF1. These data mimic the inhibitory effects of 10 nM PGE₂ and forskolin that were dependent on PKA activity. In gingival fibroblasts, the sole MAPK mediating the TGF1-stimulated CCN2/CTGF expression is JNK. Whereas forskolin reduces TGF1-stimulated expression of CCN2/CTGF by 35% and JNK activation in gingival fibroblasts, micromolar PGE₂-stimulated JNK in gingival fibroblasts and opposes the inhibitory effects of cAMP on CCN2/CTGF expression. Stimulation of the EP3 receptor with sulprostone results in a robust increase in JNK activation in these cells. Taken together, data identify two mechanisms by which TGF1-stimulated CCN2/CTGF levels in human gingival fibroblasts resist down-regulation by PGE₂: (i) cAMP cross-talk with MAPK pathways is limited in gingival fibroblasts; (ii) PGE₂ activation of the EP3 prostanoid receptor stimulates the activation of JNK.

Received for publication, November 8, 2006 , and in revised form, April 4, 2007.

^* This work was supported by National Institutes of Health NIDCR Grants R01 DE11004, K08 DE016609, and M01 RR00533. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 700 Albany St., Boston, MA 02118. Tel.: 617-638-4076; Fax: 617-638-5265; E-mail: trackman{at}bu.edu.

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				S. A. Black Jr. and P. C. Trackman Transforming Growth Factor-{beta}1 (TGF{beta}1) Stimulates Connective Tissue Growth Factor (CCN2/CTGF) Expression in Human Gingival Fibroblasts through a RhoA-independent, Rac1/Cdc42-dependent Mechanism: STATINS WITH FORSKOLIN BLOCK TGF{beta}1-INDUCED CCN2/CTGF EXPRESSION J. Biol. Chem., April 18, 2008; 283(16): 10835 - 10847. [Abstract] [Full Text] [PDF]