PMID- 15613495
OWN - NLM
STAT- MEDLINE
DCOM- 20050609
LR  - 20211203
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 288
IP  - 5
DP  - 2005 May
TI  - Mechanotransduction by integrin is essential for IL-6 secretion from endothelial 
      cells in response to uniaxial continuous stretch.
PG  - C1012-22
AB  - We previously reported that uniaxial continuous stretch in human umbilical vein 
      endothelial cells (HUVECs) induced interleukin-6 (IL-6) secretion via IkappaB 
      kinase (IKK)/nuclear factor-kappaB (NF-kappaB) 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 Ca(2+) 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 Ca(2+) concentration ([Ca(2+)](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 
      [Ca(2+)](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-kappaB signaling cascade. Another crucial factor, 
      [Ca(2+)](i) increase, may at least be required to activate PKC needed for 
      NF-kappaB activation.
FAU - Sasamoto, Akitoshi
AU  - Sasamoto A
AD  - Department of Physiology, Nagoya Univ. Graduate School of Medicine, 65 
      Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. msokabe@med.nagoya-u.ac.jp
FAU - Nagino, Masato
AU  - Nagino M
FAU - Kobayashi, Satoshi
AU  - Kobayashi S
FAU - Naruse, Keiji
AU  - Naruse K
FAU - Nimura, Yuji
AU  - Nimura Y
FAU - Sokabe, Masahiro
AU  - Sokabe M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20041221
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Estrenes)
RN  - 0 (Integrin alpha5beta1)
RN  - 0 (Interleukin-6)
RN  - 0 (Morpholines)
RN  - 0 (Oligopeptides)
RN  - 0 (Pyrrolidinones)
RN  - 0 (glycyl-arginyl-glycyl-aspartyl-asparaginyl-proline)
RN  - 112648-68-7 
      (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (CHUK protein, human)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.10 (IKBKB protein, human)
RN  - EC 2.7.11.10 (IKBKE protein, human)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.1.4.3 (Phospholipase C gamma)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - Cells, Cultured
MH  - Chromones/pharmacology
MH  - Endothelial Cells/cytology/drug effects/*metabolism
MH  - Enzyme Activation/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Estrenes/pharmacology
MH  - Humans
MH  - I-kappa B Kinase
MH  - Integrin alpha5beta1/*metabolism
MH  - Interleukin-6/*metabolism
MH  - Mechanotransduction, Cellular/drug effects/*physiology
MH  - Morpholines/pharmacology
MH  - Oligopeptides/pharmacology
MH  - Phospholipase C gamma
MH  - Protein Kinase C/antagonists & inhibitors/pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Pyrrolidinones/pharmacology
MH  - Thapsigargin/pharmacology
MH  - Type C Phospholipases/antagonists & inhibitors/pharmacology
MH  - Umbilical Veins/cytology/drug effects/metabolism
EDAT- 2004/12/23 09:00
MHDA- 2005/06/10 09:00
CRDT- 2004/12/23 09:00
PHST- 2004/12/23 09:00 [pubmed]
PHST- 2005/06/10 09:00 [medline]
PHST- 2004/12/23 09:00 [entrez]
AID - 00314.2004 [pii]
AID - 10.1152/ajpcell.00314.2004 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2005 May;288(5):C1012-22. doi: 
      10.1152/ajpcell.00314.2004. Epub 2004 Dec 21.