title: 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.
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.
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France, and Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, France.
authors.forename: Malak
authors.identifier: http://orcid.org/0000-0001-6797-932X
authors.initials: M
authors.lastname: Haidar
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France, and Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Echebli
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France, and Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, France.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France, and Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, France.
authors.forename: Everlyn
authors.initials: E
authors.lastname: Kamau
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France, and Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, France gordon.langsley@inserm.fr.
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000469:parasitology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000096:biosynthesis*; D016796:Theileria annulata / Q000502:physiology*; D014158:Transcription, Genetic; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
chemical_list: C545650:PTGER4 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053781:Transforming Growth Factor beta2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone