Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4, Leading to a Prostaglandin E2-Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages
Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4, Leading to a Prostaglandin E2-Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages
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DOI：
10.1128/iai.02975-14
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发表时间：
2015-05-01
影响因子：
3.1
通讯作者：
Langsley, Gordon
中科院分区：
文献类型：
--
作者：
Haidar, Malak;Echebli, Nadia;Langsley, Gordon
Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-beta consequently plays a central role in carcinogenesis, and a dampened TGF-beta 2 response by Theileria annulata-infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-beta 2 production, there is ablated expression of COX2 and EP4, which leads to a drop in cyclic AMP (cAMP) levels and, consequently, reduced activation of protein kinase A (PKA) and EPAC. This ablated phenotype can be rescued in attenuated macrophages by the addition of exogenous TGF-beta 2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-beta 2 therefore promotes the adhesion and invasiveness of virulent macrophages by modulating COX2, EP4, and PKIG transcription to initiate a prostaglandin E-2 (PGE2)-driven autostimulatory loop that augments PKA and EPAC activities. A virulence phenotype stemming from the double activation of PKA and EPAC is the induction of a CREB-mediated transcriptional program and the upregulation of JAM-L-and integrin 4 alpha beta 1-mediated adhesion of Theileria-infected macrophages.
