Interleukin-6 increases rat metalloproteinase-13 gene expression through stimulation of activator protein 1 transcription factor in cultured fibroblasts.
The role of IL-6 in collagen production and tissue remodeling is controversial. In Rat-1 fibroblasts, we measured the effect of IL-6 on matrix metalloproteinase-13 (MMP-13), c-jun, junB, and c-fos gene expression, binding of activator protein 1 (AP1) to DNA, amount of AP1 proteins, immunoreactive MMP-13 and TIMP-1 proteins, and Jun N-terminal kinase activity. We show that IL-6 increased MMP-13-mRNA and MMP-13 protein. These effects were exerted by acting on the AP1-binding site of the MMP-13 promoter, as shown by transfecting cells with reporter plasmids containing mutations in this element. Mobility shift assays demonstrated that IL-6 induced the DNA binding activity of AP1. This effect was accompanied by a marked increase in c-Jun, JunB, and c-Fos mRNA, as well as in c-Jun protein and its phosphorylated form. The latter is not due to increased Jun N-terminal kinase activity but to a decreased serine/threonine phosphatase activity. We conclude that IL-6 increases interstitial MMP-13 gene expression at the promoter level. This effect seems to be mediated by the induction of c-jun, junB, and c-fos gene expression, by the binding of AP1 to DNA, by increasing phosphorylated c-Jun, and by the inhibition of serine/threonine phosphatase activity. These effects of IL-6 might contribute to remodeling connective tissue.
Solís-Herruzo
J A
JA
Department of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599, USA. jasolis@h12o.es
Rippe
R A
RA
Schrum
L W
LW
de La Torre
P
P
García
I
I
Jeffrey
J J
JJ
Muñoz-Yagüe
T
T
Brenner
D A
DA
D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D016762:Genes, fos; D016758:Genes, jun; D015850:Interleukin-6 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507083:Mmp13 protein, rat