期刊
CELLULAR SIGNALLING
卷 20, 期 7, 页码 1267-1274出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.02.015
关键词
proteinase-activated receptor-2; Gq/11; p65 NF kappa B; inflammation
类别
The mechanisms underpinning the coupling of GPCRs, such as PAR-2, to the phosphorylation of p65 NF kappa B have not been investigated. In the current study we found that trypsin and the selective PAR-2 activating peptide, 2f-LIGKV-OH, stimulated large and sustained increases in the serine 536 phosphorylation of p65/RelA in a transfected skin epithelial cell line and primary keratinocytes. Parallel experiments showed that in both cell types, p65 NF kappa B phosphorylation is mediated through the selective activation of IKK2. Treatment with PKC inhibitor GF109203X or PKC alpha siRNA reduced phosphorylation at 15 min but not 30 min, whilst rottlerin, a selective PKC delta inhibitor and PKC delta siRNA reduced the response at both time points. Pre-treatment of cells with the novel Gq/11 inhibitor YM-254890 and Gq/11 siRNA caused a similar pattern of inhibition and also reduced PAR-2-mediated NF kappa B transcriptional activity. Furthermore, stimulation of cells through a novel PAR-2 mutant PAR-234-43, delayed p65 phosphorylation but was without effect on the kinetics of ERK activation. Inhibition of Gi or G12/13 pathways by pertussis toxin pre-treatment or over-expression of the RGS mutant Lsc, also did not effect NF kappa B phosphorylation. Taken together these data indicate dependency for Gq/11 in early phosphorylation of p65 NF kappa B and this subsequently affects initial NF kappa B-dependent gene transcriptional activity, however later regulation of p65 is unaffected. Overall these novel data demonstrate an IKK2-dependent, predominantly C-protein-independent pathway involved in PAR-2 regulation of NF kappa B phosphorylation in keratinocytes. (c) 2008 Elsevier Inc. All rights reserved.
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