Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells.
Epithelia from many tissues express protease-activated receptors (PARs) that play a major role in several different physiological processes. In this study, we examined their capacity to modulate IL-6, IL-8, and PGE(2) production in both the A459 and BEAS-2B cell lines and primary human bronchial epithelial cells (HBECs). All three cell types expressed PAR-1, PAR-2, PAR-3, and PAR-4, as judged by RT-PCR and immunocytochemistry. Agonist peptides corresponding to the nascent N termini of PAR-1, PAR-2, and PAR-4 induced the release of cytokines from A549, BEAS-2B, and HBECs with a rank order of potency of PAR-2 > PAR-4 > PAR-1 at 400 microM. PAR-1, PAR-2, and PAR-4 also caused the release of PGE(2) from A549 and HBECs. The PAR-3 agonist peptide was inactive in all systems tested. PAR-1, PAR-2, or PAR-4, in combination, caused additive IL-6 release, but only the PAR-1 and PAR-2 combination resulted in an additive IL-8 response. PAR peptide-induced responses were accompanied by changes in intracellular calcium ion concentrations. However, Ca(2+) ion shutoff was approximately 2-fold slower with PAR-4 than with PAR-1 or PAR-2, suggesting differential G protein coupling. Combined, these data suggest an important role for PAR in the modulation of inflammation in the lung.
Asokananthan
Nithiananthan
N
Division of Inflammation and Infectious Diseases, Department of Microbiology, Asthma & Allergy Research Institute, University of Western Australia, Nedlands, Western Australia, Australia.
Graham
Peter T
PT
Fink
Joshua
J
Knight
Darryl A
DA
Bakker
Anthony J
AJ
McWilliam
Andrew S
AS
Thompson
Philip J
PJ
Stewart
Geoffrey A
GA
D000818:Animals; D001001:Anura; D001980:Bronchi / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004338:Drug Combinations; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D010447:Peptide Hydrolases / Q000494:pharmacology; D010455:Peptides / Q000819:agonists / Q000494:pharmacology; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D004338:Drug Combinations; D015850:Interleukin-6; D016209:Interleukin-8; D010455:Peptides; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D010447:Peptide Hydrolases; D014357:Trypsin; D013917:Thrombin; C112908:protease-activated receptor 4; D015232:Dinoprostone; D002118:Calcium