Protein Kinase C-Alpha A Mediates Tnf Release Process In Rbl-2h3 Mast Cells
BRITISH JOURNAL OF PHARMACOLOGY(2005)
Abstract
1 To clarify the mechanism of mast cell TNF secretion, especially its release process after being produced, we utilized an antiallergic drug, azelastine (4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin4-yl)-1-(2H)- phthalazinone), which has been reported to inhibit TNF release without affecting its production in ionomycin-stimulated RBL-2H3 cells.2 Such inhibition was associated with the suppression of an ionomycin-induced increase in membrane-associated PKC activity rather than the suppression of Ca2+ influx, suggesting that PKC might be involved in TNF release process.3 To see whether conventional PKC family (cPKCs) are involved, we investigated the effects of a selective cPKC inhibitor (Go6976) and an activator ( thymeleatoxin) on TNF release by adding them 1 h after cell stimulation. By this time, TNF mRNA expression had reached its maximum. Go6976 markedly inhibited TNF release, whereas thymeleatoxin enhanced it, showing a key role of cPKC in TNF post-transcriptional process, possibly its releasing step.4 To determine which subtype of cPKCs could be affected by azelastine, Western blotting and live imaging by confocal microscopy were conducted to detect the translocation of endogenous cPKC (alpha, beta I and beta II) and transfected GFP-tagged cPKC, respectively. Both methods clearly demonstrated that 1 mu M azelastine selectively inhibits ionomycin-triggered translocation of aPKC without acting on bI or beta IIPKC.5 In antigen-stimulated cells, such a low concentration of azelastine did not affect either alpha PKC translocation or TNF release, suggesting a functional link between alpha PKC and the TNF-releasing step.6 These results suggest that alpha PKC mediates the TNF release process and azelastine inhibits TNF release by selectively interfering with the recruitment of alpha PKC in the pathway activated by ionomycin in RBL-2H3 cells.
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Key words
conventional protein kinase C, RBL-2H3 mast cell, tumor necrosis factor
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