Interleukin-6 increases rat metalloproteinase-13 gene expression through Janus kinase-2-mediated inhibition of serine/threonine phosphatase-2A.
Interleukin-6 (IL-6) increases metalloproteinase-13 (MMP-13) gene expression by increasing phosphorylated c-Jun and by inhibiting serine/threonine phosphatase-2A (PP2A) activity. We investigated the mechanisms by which IL-6 induces c-Jun phosphorylation and PP2A inactivation in Rat-1 fibroblasts. We show that IL-6 increased MMP-13 mRNA, phosphorylated c-Jun, and activator protein 1 (AP1) binding activity without increasing c-Jun-N-terminal kinase (JNK) activity. These effects did not seem to be mediated by ERK, p38 MAP kinase, phosphatidylinositol-3-kinase, calmoduline-dependent protein kinase, protein kinase C (PKC) or protein kinase A since inhibition with specific inhibitors did not abrogate these effects. IL-6 increases PP2A catalytic subunit tyrosine phosphorylation. Inhibition of the tyrosine kinase Jak2, with the specific inhibitor AG490, abrogated this effect. Likewise, this Jak2 inhibitor blocked the effects of IL-6 on c-Jun phosphorylation, AP1 binding activity and metalloproteinase-13 gene expression. We conclude that IL-6 increases MMP-13 gene expression by activation of Jak2, resulting in tyrosine phosphorylation of the catalytic subunit of PP2A, which in turn decreases PP2A activity and prolongs c-Jun phosphorylation.
de la Torre
Paz
P
Department of Medicine, Gastroenterology, Research Center, Hospital Universitario 12 de Octubre, Avd. Córdoba, 28041-Madrid, Spain.
Díaz-Sanjuán
Teresa
T
García-Ruiz
Inmaculada
I
Esteban
Elena
E
Canga
Fernando
F
Muñoz-Yagüe
Teresa
T
Solís-Herruzo
José A
JA
D000818:Animals; D017364:Collagenases / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015850:Interleukin-6 / Q000502:physiology*; D053614:Janus Kinase 2; D053509:Matrix Metalloproteinase 13; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D015854:Up-Regulation
D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat