Induction of MMP-9 release from human dermal fibroblasts by thrombin: involvement of JAK/STAT3 signaling pathway in MMP-9 release.
BACKGROUND
It has been recognized that dermal fibroblasts and matrix metalloproteases (MMP) play crucial roles in wound healing process in skin. Thrombin was found to stimulate IL-8 release from human dermal fibroblasts (HDFs). However, little is known of the effect of thrombin on secretion of MMPs from dermal fibroblasts. In the present study, the influence of thrombin on proMMP-2 and proMMP-9 activity release from primary cultured HDFs, and its potential signaling pathways were investigated.


RESULTS
The results showed that thrombin induced proMMP-9, but not proMMP-2 release from HDFs in a dose dependent manner at 6 h following incubation. Thrombin also upregulated expression of proMMP-9 mRNA in HDFs. Hirudin completely abolished the action of thrombin on HDFs. An agonist peptide of protease-activated receptor-1, SFLLR-NH2 stimulated an enhanced release of proMMP-9 from HDFs. AG490, an inhibitor of STAT3 inhibited basal and thrombin-provoked proMMP-9 release and phosphorylation of STAT3. PD98059, an inhibitor of MAPK and LY294002, an inhibitor PI3K failed to significantly inhibit thrombin induced proMMP-9 release.


CONCLUSIONS
Thrombin is a potent stimulus of proMMP-9 release from HDFs. Thrombin induced proMMP-9 release is most likely through activation of PAR-1. JAK/STAT3 signaling pathway is involved in proMMP-9 release from HDFs.
Wang
Li
L
The First Affiliated Hospital, Shantou University Medical College, Shantou, China. pfkwangli@163.com <pfkwangli@163.com>
Luo
Jianmin
J
He
Shaoheng
S
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018093:Gelatinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation; D014945:Wound Healing / Q000502:physiology
D004792:Enzyme Precursors; D044462:Receptors, Proteinase-Activated; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053613:Janus Kinase 1; D013917:Thrombin; D018093:Gelatinases; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020780:Matrix Metalloproteinase 9