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1 Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
2 Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; ICORP, JST, Cell Mechanosensing Project, Nagoya, Japan
* To whom correspondence should be addressed. E-mail: msokabe{at}med.nagoya-u.ac.jp.
We previously reported that uni-axial continuous stretch in human umbilical vein endothelial cells (HUVECs) induced interleukin-6 (IL-6) secretion via I
B kinase (IKK)/ nuclear factor-B (NF-B) activation. The aim of this study was to clarify the upstream signaling mechanism responsible for this phenomenon. The stretch-induced IKK activation and IL-6 secretion were inhibited by an application of 
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1 integrin inhibitory peptide (GRGDNP), phosphatidylinositol 3-kinase inhibitor (LY294002), phospholipase C
inhibitor (U73122) or protein kinase C inhibitor (H7). Although depletion of intra- or extra-cellular Ca2+ pool by thapsigargin (TG) or EGTA, respectively, showed little effect, an application of TG/EGTA mixture significantly inhibited the 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 TG/EGTA mixture, indicating that both the integrin activation and [Ca2+]i rise are crucial factors for the stretch-induced IKK activation and following IL-6 secretion in HUVECs. Furthermore, while PKC activity was inhibited by TG/EGTA mixture, GRGDNP, LY294002 or U73122, PLC activity was retarded by GRGDNP or LY294002. These results indicate that continuous-stretch induced IL-6 secretion in HUVECs depends upon the outside-in signaling via integrins followed by PI3-K/PLC/PKC/IKK/NF-B signaling cascade. Another crucial factor, a [Ca2+]i increase, may at least be required to activate PKC that is needed for NF-B activation.
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