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.
You have requested a machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Neither BioOne nor the owners and publishers of the content make, and they explicitly disclaim, any express or implied representations or warranties of any kind, including, without limitation, representations and warranties as to the functionality of the translation feature or the accuracy or completeness of the translations.
Translations are not retained in our system. Your use of this feature and the translations is subject to all use restrictions contained in the Terms and Conditions of Use of the BioOne website.
Vol. 178 • No. 6