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Am J Physiol Cell Physiol 288: C1012-C1022, 2005. First published December 21, 2004; doi:10.1152/ajpcell.00314.2004
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VASCULAR BIOLOGY

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

Akitoshi Sasamoto,1,2 Masato Nagino,1 Satoshi Kobayashi,1 Keiji Naruse,2,3 Yuji Nimura,1 and Masahiro Sokabe2,3,4

1Division of Surgical Oncology, Department of Surgery, and 2Department of Physiology, Nagoya University Graduate School of Medicine; and 3Cell Mechanosensing Project, International Cooperative Research Project, Japan Science and Technology Agency, Nagoya; and 4Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Japan

Submitted 8 July 2004 ; accepted in final form 17 December 2004

We previously reported that uniaxial continuous stretch in human umbilical vein endothelial cells (HUVECs) induced interleukin-6 (IL-6) secretion via I{kappa}B kinase (IKK)/nuclear factor-{kappa}B (NF-{kappa}B) 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 {alpha}5{beta}1 integrin-inhibitory peptide (GRGDNP), phosphatidylinositol 3-kinase inhibitor (LY-294002), phospholipase C-{gamma} 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-{gamma} 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-{gamma}-PKC-IKK-NF-{kappa}B signaling cascade. Another crucial factor, [Ca2+]i increase, may at least be required to activate PKC needed for NF-{kappa}B activation.

nuclear factor-{kappa}B; phosphatidylinositol 3-kinase; phospholipase C-{gamma}; protein kinase C; intracellular Ca2+ concentration


Address for reprint requests and other correspondence: M. Sokabe, Department of Physiology, Nagoya Univ. Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (E-mail: msokabe{at}med.nagoya-u.ac.jp)




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