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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.

Infection and immunity (2015-02-19)
Malak Haidar, Nadia Echebli, Ying Ding, Everlyn Kamau, Gordon Langsley
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 E2 (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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Prostaglandin E2, ≥93% (HPLC), synthetic
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cAMP Enzyme Immunoassay Kit, Direct
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2,5-Dimethyl-celecoxib, ≥98% (HPLC)
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Protein Kinase A inhibitor fragment 14-22, myristoylated trifluoroacetate salt, ≥90% (HPLC), lyophilized powder
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ESI-09, ≥98% (HPLC)
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Anti-PTGER4 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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