TGF-β induced hyaluronan synthesis in orbital fibroblasts involves protein kinase C βII activation in vitro

Hwai Shi Wang*, Wen Hsiu Tung, Kam Tsun Tang, Yi Kuei Wong, Ging Jye Huang, Jiahn Chun Wu, Yi Jhih Guo, Chin Chang Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Graves' ophthalmopathy is accompanied by hyaluronan (HA) accumulation in the orbital space and infiltration of immunocompetent cells and cytokines, including IFN-γ, IL-1β, and TGF-β. We examined the signal transduction pathways by which TGF-β induces HA synthesis in normal orbital fibroblasts, orbital fibroblasts from patients with Graves' ophthalmopathy, and abdominal fibroblasts. Calphostin C inhibited the stimulation of HA synthesis by TGF-β. Phorbol 12-myristate 13-acetate (PMA) activation of PKC stimulated HA production. The effects of TGF-β and PMA were not synergistic. Stimulation by TGF-β and PMA were dependent on protein synthesis and their effects were inhibited by cycloheximide. Since TGF-β-induced HA synthesis was inhibited by BAPTA or by PKC inhibitors, a calcium-dependent PKC was most likely involved. The PKA inhibitor H-89 enhanced TGF-β- and PMA-induced HA synthesis, thus showing that communication between the PKA and PKC pathways was evident. TGF-β stimulated the translocation of PKCβII to the cell membrane. PKCβII, a key enzyme in the regulation of HA synthesis by TGF-β, might be an appropriate target for therapeutic compounds to be used to treat Graves' ophthalmopathy accompanied by inflammation.

Original languageEnglish
Pages (from-to)256-267
Number of pages12
JournalJournal of Cellular Biochemistry
Volume95
Issue number2
DOIs
StatePublished - 15 May 2005

Keywords

  • Graves' ophthalmopathy
  • Hyaluronan
  • Orbital fibroblasts
  • PKCβII
  • TGF-β

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