PAR-2 activation and LPS synergistically enhance inflammatory signaling in airway epithelial cells by raising PAR expression level and interleukin-8 release.
Protease-activated receptors (PARs) are involved in the contribution of airway epithelial cells to the development of inflammation by release of pro- and anti-inflammatory mediators. Here, we evaluated in epithelial cells the influence of LPS and continuous PAR activation on PAR expression level and the release of the proinflammatory chemokine IL-8. We studied primary human small airway epithelial cells and two airway epithelial cell lines, A549 and HBE cells. LPS specifically upregulated expression of PAR-2 but not of PAR-1. Exposure of epithelial cells to PAR-1 or PAR-2 agonists increased the PAR-1 expression level. The PAR-2 agonist exhibited higher potency than PAR-1 activators. However, the combined exposure of epithelial cells to LPS and PAR agonists abrogated the PAR-1 upregulation. The PAR-2 expression level was also upregulated after exposure to PAR-1 or PAR-2 agonists. This elevation was higher than the effect of PAR agonists on the PAR-1 level. In contrast to the PAR-1 level, the PAR-2 level remained elevated under concomitant stimulation with LPS and PAR-2 agonist. Furthermore, activation of PAR-2, but not of PAR-1, caused production of IL-8 from the epithelial cells. Interestingly, both in the epithelial cell line and in primary epithelial cells, there was a potentiation of the stimulation of the IL-8 synthesis and release by PAR-2 agonist together with LPS. In summary, these results underline the important role of PAR-2 in human lung epithelial cells. Moreover, our study shows an intricate interplay between LPS and PAR agonists in affecting PAR regulation and IL-8 production.
Ostrowska
Ewa
E
Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Strasse 44, D-39120, Magdeburg, Germany.
Sokolova
Elena
E
Reiser
Georg
G
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D016209:Interleukin-8; D008070:Lipopolysaccharides; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D002118:Calcium