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
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
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DOI：
10.1074/jbc.m610432200
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发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Trackman, Philip C.
中科院分区：
文献类型：
--
作者：
Black, Samuel A., Jr.;Palamakumbura, Amitha H.;Trackman, Philip C.
前列腺素E-2阻断肺和肾成纤维细胞中转化生长因子TGF β 1诱导的CCN 2/CTGF表达。牙龈组织中PGE（2）水平高，而纤维化牙龈过度生长中CCN 2/CTGF表达升高。在PGE 2存在下，牙龈成纤维细胞CCN 2/CTGF表达使我们比较了从不同组织培养的成纤维细胞中CCN 2/CTGF表达的调节。数据表明，TGF β 1诱导的人肺和肾系膜细胞中CCN 2/CTGF的表达被10 nM PGE 2抑制，而人牙龈成纤维细胞具有抗性。10 nM PGE 2增加肺中cAMP的积累，但不增加牙龈成纤维细胞中cAMP的积累，牙龈成纤维细胞需要1 μ M PGE 2来升高cAMP。微摩尔PGE 2仅轻微降低牙龈细胞中TGF β 1刺激的CCN 2/CTGF水平。用布他前列素激活EP 2前列腺素受体阻断TGF β 1刺激的肺成纤维细胞中CCN 2/CTGF表达，但不阻断牙龈成纤维细胞中CCN 2/CTGF表达。在肺成纤维细胞中，PGE 2、布他前列素或毛喉素对TGF β 1刺激的CCN 2/CTGF的抑制是由于cAMP依赖性的p38、ERK和JNK MAP激酶抑制。抑制任何两种MAPK完全阻断由TGF β 1刺激的CCN 2/CTGF表达。这些数据模拟了依赖于PKA活性的10 nM PGE 2和毛喉素的抑制作用。在牙龈成纤维细胞中，介导TGF β 1刺激的CCN 2/CTGF表达的唯一MAPK是JNK。而Forskolin降低TGF β 1刺激的CCN 2/CTGF表达35%和牙龈成纤维细胞中JNK的活化，微摩尔PGE 2刺激的牙龈成纤维细胞中JNK，并对抗cAMP对CCN 2/CTGF表达的抑制作用。用硫前列酮刺激EP 3受体导致这些细胞中JNK活化的稳健增加。总而言之，数据确定了人牙龈成纤维细胞中TGF β 1刺激的CCN 2/CTGF水平抵抗PGE 2下调的两种机制：（i）牙龈成纤维细胞中cAMP与MAPK途径的串扰受到限制;（ii）PGE 2激活EP 3前列腺素受体刺激JNK的激活。
Prostaglandin E-2 blocks transforming growth factor TGF beta 1-induced CCN2/CTGF expression in lung and kidney fibroblasts. PGE(2) 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 TGF beta 1-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 mu M PGE2 to elevate cAMP. Micromolar PGE2 only slightly reduces the TGF beta 1-stimulated CCN2/CTGF levels in gingival cells. EP2 prostaglandin receptor activation with butaprost blocks the TGF beta 1-stimulated expression of CCN2/CTGF expression in lung, but not gingival, fibroblasts. In lung fibroblasts, inhibition of the TGF beta 1-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 TGF beta 1. 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 TGF beta 1-stimulated CCN2/CTGF expression is JNK. Whereas forskolin reduces TGF beta 1-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 TGF beta 1-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.