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Tachykinin receptor modulation of cyclooxygenase‐2 expression in human polymorphonuclear leucocytes
Author(s) -
Gallicchio M,
Benetti E,
Rosa AC,
Fantozzi R
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00033.x
Subject(s) - receptor , neurokinin a , phosphorylation , kinase , cyclooxygenase , p38 mitogen activated protein kinases , tachykinin receptor , stimulation , western blot , substance p , signal transduction , biology , chemistry , pharmacology , protein kinase a , microbiology and biotechnology , endocrinology , biochemistry , neuropeptide , enzyme , gene
Mandarin translation of abstract Background and purpose: We investigated the ability of natural and synthetic selective NK receptors agonists and antagonists to modulate cyclooxygenase‐2 (COX‐2) expression in human polymorphonuclear leucocytes (PMNs). Experimental approach: The presence of all three tachykinin in PMNs was assessed by Western blot and PCR techniques. Natural and synthetic ligands selective for the tachykinin receptors were used to modulate COX‐2 protein (measured with Western blotting) and activity [as prostaglandin E 2 (PGE 2 ) output]. Effects of substance P (SP) on phosphorylation of mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) activation were studied to analyse the signalling pathway involved in COX‐2 up‐regulation mediated by SP. Key results: Stimulation of NK receptors with the natural ligands SP, neurokinin A (NKA) and neurokinin B, in the pmol·L −1 ‐µmol·L −1 concentration range, modulated COX‐2 expression and PGE 2 release in a concentration‐ and time‐dependent manner. Experiments with synthetic selective agonists [Sar 9 , Met(O 2 ) 11 ]SP, [β‐Ala 8 ] NKA(4‐10), senktide or selective antagonists L703,606, SR48,968 or SR142801, confirmed that COX‐2 up‐regulation was mediated by NK receptors. We found that mainly p38, p42 and p46 MAPKs were phosphorylated by SP and SB202190, PD98059 and SP600125, which are selective inhibitors of these kinases, blocked SP‐induced COX‐2 expression. SP also induced nuclear translocation of NF‐κB concentration‐dependently, with a maximum effect at 1 nmol·L −1 . Conclusions and implications: Human PMNs possess functional NK 1 , NK 2 and NK 3 receptors, which mediate the induction of COX‐2 expression and NF‐κB activation by SP. Mandarin translation of abstract