Signal transduction for formation/release of interleukin-8 caused by a PAR2-activating peptide in human lung epithelial cells.
Proteinase-activated receptor-2 (PAR2) plays a dual role in the respiratory system, being pro- and anti-inflammatory. In human lung epithelial cells (A549), PAR2 activation causes release of interleukin-8 (IL-8) in addition to prostaglandin E(2) (PGE(2)). In the present study, we thus investigated PAR2-triggered signal transduction pathways causing IL-8 formation in A549 cells. SLIGRL-NH(2), a PAR2-activating peptide, but not LSIGRL-NH(2), a scrambled peptide, elicited release of IL-8 from A549 cells for 18 h, as measured by the ELISA method, an effect being suppressed by inhibitors of MEK, JNK, EGF receptor-tyrosine kinase (EGFR-TK), Src, pan-tyrosine kinases and protein kinase C, but not p38 MAP kinase or cyclooxygenase. SLIGRL-NH(2) also up-regulated IL-8 at protein and mRNA levels, as determined by Western blotting and RT-PCR, respectively. The PAR2-triggered up-regulation of IL-8 protein and mRNA was blocked by an inhibitor of MEK, but not clearly by inhibitors of JNK and EGFR-TK. SLIGRL-NH(2) actually phosphorylated JNK as well as ERK, the JNK activation being resistant to inhibitors of Src, pan-tyrosine kinases, protein kinase C and EGFR-TK. Our data suggest that PAR2-triggered IL-8 formation involves transcriptional up-regulation of IL-8 via the MEK-ERK pathway, while the JNK and EGF receptor pathways might rather contribute to a post-transcriptional process for the release of IL-8.
Moriyuki
Kazumi
K
Division of Physiology and Pathophysiology, School of Pharmacy, Kinki University, Higashi-Osaka 577-8502, Japan.
Nagataki
Mami
M
Sekiguchi
Fumiko
F
Nishikawa
Hiroyuki
H
Kawabata
Atsufumi
A
D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016209:Interleukin-8; D010455:Peptides; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone