Upregulation of tenascin-C expression by IL-13 in human dermal fibroblasts via the phosphoinositide 3-kinase/Akt and the protein kinase C signaling pathways.
In this study, we examined the genes targeted by IL-13 in human dermal fibroblasts using a cDNA microarray. We focused on the tenascin-C (TN-C) gene, which was identified as one of the genes induced by IL-13. IL-13 induced transcriptional activity of TN-C. IL-13-mediated TN-C expression was inhibited by treatment with wortmannin or LY294002, or Calphostin C. IL-13 induced the phosphorylation of the phosphoinositide 3-kinase (PI3K) regulatory subunit p85, induced tyrosine phosphorylation of Akt, upregulated Akt kinase activity, and activated protein kinase C (PKC)-delta and -epsilon. The IL-13-induced increase in TN-C protein expression was abrogated by the transfection of a dominant-negative mutant of Akt, PKC-delta, or PKC-epsilon. In conclusion, we showed that the PI3K/Akt and/or PKC signaling pathways are essential for the IL-13-mediated increase in TN-C. Both serum levels of IL-13 and the expression levels of TN-C in the dermis are increased in patients with systemic sclerosis. Our findings suggest that the expression of TN-C is upregulated in this disease due to IL-13 signaling, and that a blockade of the PI3K or PKC signaling pathway may also have therapeutic value by reducing the amount of TN-C produced during fibrosis.
Jinnin
Masatoshi
M
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Ihn
Hironobu
H
Asano
Yoshihide
Y
Yamane
Kenichi
K
Trojanowska
Maria
M
Tamaki
Kunihiko
K
D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D019063:Tenascin / Q000235:genetics*; D015854:Up-Regulation; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D018793:Interleukin-13; D009025:Morpholines; D009281:Naphthalenes; D019063:Tenascin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; C058819:calphostin C; D000077191:Wortmannin