Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4 , Leading to a Prostaglandin E 2 -Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages

Abstract

ABSTRACT Transforming growth factor beta (TGF-β) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-β consequently plays a central role in carcinogenesis, and a dampened TGF-β2 response by Theileria annulata -infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-β2 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-β2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-β2 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 4αβ1-mediated adhesion of Theileria -infected macrophages.