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Pleural Mesothelial Cells Express Both BLT2 and PPAR and Mount an Integrated Response to Pleural Leukotriene B₄¹

Elisabetta Pace^2,*, Maria Ferraro, Christopher H. Mody, Mario R. Melis^*, Valeria Scafidi, Anna Bonanno^*, Mirella Profita^*, Antonino Giarratano and Mark Gjomarkaj^*

^* Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, and Dipartimento di Anestesiologia, Rianimazione e delle Emergenze, Università degli Studi di Palermo, Palermo, Italy. Departments of Internal Medicine and Microbiology and Infectious Disease, University of Calgary, Alberta, Canada; and Dipartimento di Biopatologia e Metodologie Biomediche, Università degli Studi di Palermo, Palermo, Italy

Leukotriene B₄ (LTB₄) plays a crucial role in the recruitment of neutrophils into the pleural space. We identified for the first time the mechanisms by which LTB₄ interacts with mesothelial cells and recruits neutrophils in the pleural compartment. Primary pleural mesothelial cells express both the proinflammatory receptor for LTB₄ BLT2, and the anti-inflammatory receptor for LTB₄, PPAR. Parapneumonic pleural effusions highly increase BLT2 expression and, via BLT2 activation, increase the adhesion between mesothelial cells and neutrophils and the expression of ICAM-1 on mesothelial cells. The block of PPAR further increases both cell adhesion and ICAM-1 expression. BLT2 activation promotes the activation, on mesothelial cells, of STAT-1 but not the activation of NF-B transcription factor. The increase of ICAM-1 expression is achieved via increased tyrosine phosphorylation activity since herbimycin, a tyrosine kinase inhibitor, reduces and since Na orthovanadate, a tyrosine phosphatase inhibitor, further increases ICAM-1 expression. This study demonstrates that pleural mesothelial cells, expressing both proinflammatory and anti-inflammatory LTB₄ receptors, are able to mount an integrated response to LTB₄ with a prevalence of BLT2 activities in the presence of an inflammatory milieu within the pleura.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Italian National Research Council and by the Alberta Lung Association.

² Address correspondence and reprint requests to Dr. Elisabetta Pace, Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa, Palermo, Italy. E-mail address: pace{at}ibim.cnr.it

³ Abbreviations used in this paper: LTB₄, leukotriene B₄; GPCR, G protein-coupled transmembrane domain receptor; PF, pleural fluid; ChiP, chromatin immunoprecipitation.