Mechanotransduction by integrin is essential for IL-6 secretion from endothelial cells in response to uniaxial continuous stretch

Akitoshi Sasamoto, Masato Nagino, Satoshi Kobayashi, Keiji Naruse, Yuji Nimura, Masahiro Sokabe

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

We previously reported that uniaxial continuous stretch in human umbilical vein endothelial cells (HUVECs) induced interleukin-6 (IL-6) secretion via IκB kinase (IKK)/nuclear factor-κB (NF-κB) activation. The aim of the present study was to clarify the upstream signaling mechanism responsible for this phenomenon. Stretch-induced IKK activation and IL-6 secretion were inhibited by application of α5β1 integrin-inhibitory peptide (GRGDNP), phosphatidylinositol 3-kinase inhibitor (LY-294002), phospholipase C-γ inhibitor (U-73122), or protein kinase C inhibitor (H7). Although depletion of intra- or extracellular Ca2+ pool using thapsigargin (TG) or EGTA, respectively, showed little effect, a TG-EGTA mixture significantly inhibited stretch-induced IKK activation and IL-6 secretion. An increase in the intracellular Ca2+ concentration ([Ca2+]i) upon continuous stretch was observed even in the presence of TG, EGTA, or GRGDNP, but not in a solution containing the TG-EGTA mixture, indicating that both integrin activation and [Ca2+]i rise are crucial factors for stretch-induced IKK activation and after IL-6 secretion in HUVECs. Furthermore, while PKC activity was inhibited by the TG-EGTA mixture, GRGDNP, LY-294002, or U-73122, PLC-γ activity was retarded by GRGDNP or LY-294002. These results indicate that continuous stretch-induced IL-6 secretion in HUVECs depends on outside-in signaling via integrins followed by a PI3-K-PLC-γ-PKC-IKK-NF-κB signaling cascade. Another crucial factor, [Ca2+]i increase, may at least be required to activate PKC needed for NF-κB activation.

Original languageEnglish
Pages (from-to)C1012-C1022
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number5 57-5
DOIs
Publication statusPublished - May 1 2005
Externally publishedYes

Keywords

  • Intracellular CA concentration
  • Nuclear factor-κb
  • Phosphatidylinositol 3-kinase
  • Phospholipase C-γ
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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