Induction of interleukin-8 secretion and activation of ERK1/2, p38 MAPK signaling pathways by thrombin in dermal fibroblasts

It was reported that thrombin could induce IL-8 secretion from human dermal fibroblasts (HDFs) through activation of proteinase activated receptor (PAR)-1. However, little is known of intracellular signaling pathways involved in the event. In the present study, expression of PARs in primarily cultur...

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Bibliographic Details
Published in:The international journal of biochemistry & cell biology 2006, Vol.38 (9), p.1571-1583
Main Authors: Wang, Li, Luo, Jianmin, Fu, Yiling, He, Shaoheng
Format: Article
Language:English
Subjects:
Adolescent
Adult
Butadienes - pharmacology
Chromones - pharmacology
Fibroblasts - drug effects
Fibroblasts - metabolism
Flavonoids - pharmacology
Human dermal fibroblast
Humans
IL-8
Imidazoles - pharmacology
Interleukin-8 - secretion
Male
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Morpholines - pharmacology
Nitriles - pharmacology
p38 Mitogen-Activated Protein Kinases - metabolism
PAR-1
Pyridines - pharmacology
Receptors, Proteinase-Activated - physiology
Signal transduction
Signal Transduction - drug effects
Skin - cytology
STAT3 Transcription Factor - metabolism
Thrombin
Thrombin - pharmacology
Tyrphostins - pharmacology
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Summary:It was reported that thrombin could induce IL-8 secretion from human dermal fibroblasts (HDFs) through activation of proteinase activated receptor (PAR)-1. However, little is known of intracellular signaling pathways involved in the event. In the present study, expression of PARs in primarily cultured HDFs was determined by flow cytometry analysis and reverse transcription polymerase chain reaction (RT-PCR), levels of IL-8 were determined by using ELISA and signaling pathways were examined by using Western blot. It was found that HDFs express PAR-1 and PAR-3, and thrombin induces approximately 7.4-fold increase in IL-8 secretion from HDFs. Hirudin and a PAR-1 blocking antibody completely abolish the action of thrombin. It was also found that PD98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor and U0126, an inhibitor of extracellular signal-regulated kinase (ERK) blocks thrombin-induced phosphorylation of ERK1/2 and IL-8 secretion, indicating the involvement of MAPK/ERK signaling pathway in thrombin-induced IL-8 secretion. p38 MAPK pathway appears also being involved as SB203580, a selective inhibitor of p38 MAPK inhibit phosphorylation of p38 MAPK and thrombin-induced IL-8 secretion. Furthermore, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway, but not phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway may also be activated by thrombin. In conclusion, thrombin potently induce IL-8 release via PAR-1 from HDFs. Thrombin elicited IL-8 release is predominantly conducted through MAPK/ERK and p38 MAPK signaling pathways. Discovery of the signaling pathways of thrombin in HDFs may help to understand the role of thrombin in inflammation and tissue remodeling.
ISSN:1357-2725
1878-5875
DOI:10.1016/j.biocel.2006.03.016