Signaling mechanisms involved in protease-activated receptor-1-mediated interleukin-6 production by human gingival fibroblasts.

Human gingival fibroblasts (HGFs) express protease-activated receptor-1 (PAR-1) at high levels. In cultured HGFs, we studied the signaling pathway of thrombin-induced interleukin-6 (IL-6) production. The PAR-1 agonist peptide SFLLRN mimicked the thrombin-induced IL-6 production in the presence of amastatin, an aminopeptidase inhibitor. Thrombin or a combination of SFLLRN and amastatin also strikingly induced the expression of IL-6 mRNA. Although continuous exposure of HGFs to thrombin rapidly desensitized Ca(2+) signaling, the cells did not lose their ability to produce IL-6 in response to thrombin. Similarly, although treatment of HGFs with BAPTA-AM [1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester], an intracellular Ca(2+) chelator, markedly attenuated the thrombin-induced increase in intracellular Ca(2+) concentration, the same treatment did not suppress the thrombin-induced IL-6 production. However, thrombin-induced IL-6 production was strongly inhibited by the p38 mitogen-activated protein (MAP) kinase and tyrosine kinase inhibitors, and Western blotting analyses showed that thrombin stimulates p38 MAP kinase phosphorylation. Specific inhibitors that inhibit extracellular signal-regulated kinase 1/2 kinase, phosphatidylinositol 3-kinase, and RhoA kinase also partially suppressed the thrombin-induced IL-6 production, but the effects were smaller than those of the p38 MAP and tyrosine kinase inhibitors. Thus, thrombin induces HGFs to produce IL-6 by activating PAR-1, and the tyrosine kinase- and p38 MAP kinase-dependent pathways, rather than the Ca(2+) signaling pathway, may play a crucial role in the IL-6 production.

Tanaka N ，Morita T ，Nezu A ，Tanimura A ，Mizoguchi I ，Tojyo Y ... -  《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》

Thrombin-induced IL-6 production in human synovial fibroblasts is mediated by PAR1, phospholipase C, protein kinase C alpha, c-Src, NF-kappa B and p300 pathway.

Chiu YC ，Fong YC ，Lai CH ，Hung CH ，Hsu HC ，Lee TS ，Yang RS ，Fu WM ，Tang CH ... -  《MOLECULAR IMMUNOLOGY》

Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways.

Amin MA ，Mansfield PJ ，Pakozdi A ，Campbell PL ，Ahmed S ，Martinez RJ ，Koch AE ... -  《ARTHRITIS AND RHEUMATISM》

Suppression of lipopolysaccharide-induced cytokine production of gingival fibroblasts by a soybean, Kunitz trypsin inhibitor.

Kobayashi H ，Yoshida R ，Kanada Y ，Fukuda Y ，Yagyu T ，Inagaki K ，Kondo T ，Kurita N ，Suzuki M ，Kanayama N ，Terao T ... -  《JOURNAL OF PERIODONTAL RESEARCH》

Regulation of endothelin-1-induced interleukin-6 production by Ca2+ influx in human airway smooth muscle cells.

Iwata S ，Ito S ，Iwaki M ，Kondo M ，Sashio T ，Takeda N ，Sokabe M ，Hasegawa Y ，Kume H ... -  《-》