title: Mast cells and ionizing radiation induce a synergistic expression of inflammatory genes in endothelial cells by a mechanism involving p38α MAP kinase and (p65) NF-κB activation.
abstract: Vascular endothelium is a key compartment involved in the development of normal tissue toxicity associated with cancer radiation therapy, i.e., acute inflammation and late fibrosis. Radiation-induced endothelial cell activation has been extensively studied, and activated endothelial cells are characterized by increased expression of inflammatory mediators and adhesion molecules, and activation of the coagulation and thrombosis pathways. However, little is known about the role of vascular endothelium interaction with resident immune cells, such as mast cells on its response to irradiation. Here, we report that endothelial exposure to mast cell conditioned medium and irradiation induces a synergistic expression of many inflammatory genes including interleukin-6 and interleukin-8, CXCL2 and E-selectin. This synergy is blocked by the histamine H1 receptor antagonist mepyramine and partially mimicked by exogenous histamine addition before irradiation. Using pharmacological and molecular inhibition approaches, we show the p38α MAP kinase and p65 (NF-κB) dependence of the synergy. Moreover, our data show a link between both pathways, with p65 (NF-κB) being downstream of p38. These data highlight the possible exacerbation of the radiation-induced endothelial inflammatory response by its interactions with immune cells. It also suggest that p38α MAP kinase and p65 (NF-κB) inhibition in vascular endothelium may limit excessive tissue inflammation induced by radiation therapy, and thereby limit the associated acute and late tissue damage.
authors.affiliation: Laboratory of Radiopathology and Experimental Therapies, Institute for Radiological Protection and Nuclear Safety, 92265 Fontenay-aux-Roses, France.
authors.forename: Karl
authors.initials: K
authors.lastname: Blirando
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hneino
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martelly
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
authors.forename: Agnès
authors.initials: A
authors.lastname: François
mesh_terms: D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D020868:Gene Silencing; D006632:Histamine / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D017077:Culture Media, Conditioned; D006632:Histamine; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051996:Transcription Factor RelA; D020764:cdc42 GTP-Binding Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2