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ICAM-1 Signal Transduction in Cells Stimulated with Neutrophil Elastase

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Abstract

Neutrophil elastase, which enhances intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells, plays an important role in ischemia/reperfusion injury. Here, we investigated signal transduction of ICAM-1 expression in endothelial cells stimulated by neutrophil elastase. Pretreatment of animals with the neutrophil elastase inhibitor, ONO-5046.Na significantly decreased the number of neutrophils or Mac-1+ (CD11b/CD18) cells in ischemic liver lobes after reperfusion. ICAM-1 expression in the rat endothelial cell line (WK-5) was significantly upregulated after stimulation with neutrophil elastase, but this reaction was inhibited by the neutrophil elastase inhibitor ONO-5046.Na. ICAM-1 mRNA expression, which is induced by neutrophil elastase in a dose-dependent manner, was repressed by the α1-protease inhibitor. ICAM-1 expression, stimulated by neutrophil elastase, was partially reduced by a diacylglycerol kinase inhibitor and protein kinase C inhibitor, but was completely inhibited by a phospholipase C inhibitor, cytosolic Ca2+ chelator, calmodulin antagonist, and nuclear transcription factor kappa B inhibitor. Binding of 125I-neutrophil elastase to WK-5 cells was competitively inhibited by the addition of unlabeled neutrophil elastase. The neutrophil elastase inhibitor significantly reduces ICAM-1 expression and Mac-1+ cell accumulation in ischemic liver lobes after reperfusion. Neutrophil elastase stimulates ICAM-1 expression in endothelial cells by intracellular signal transduction via activation of diacylglycerol kinase, protein kinase C, phospholipase C, Ca2+-calmodulin, and nuclear transcription factor kappa B.

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Authors and Affiliations

  1. Department of Surgery II, Kumamoto University Medical School, Honjo 1-1-1, Kumamoto, 860-8556, Japan

    Kohjiroh Ishihara, Yasuo Yamaguchi, Shinichiro Uchino, Takashi Furuhashi, Katsutaka Mori & Michio Ogawa

  2. First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

    Shinwa Yamada

  3. Department of Education, Kumamoto University, Kumamoto, Japan

    Shinichi Kihara

Authors
  1. Kohjiroh Ishihara
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  2. Yasuo Yamaguchi
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  3. Shinichiro Uchino
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  4. Takashi Furuhashi
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Correspondence to Kohjiroh Ishihara.

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Ishihara, K., Yamaguchi, Y., Uchino, S. et al. ICAM-1 Signal Transduction in Cells Stimulated with Neutrophil Elastase. Dig Dis Sci 51, 2102–2112 (2006). https://doi.org/10.1007/s10620-006-9178-1

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  • DOI: https://doi.org/10.1007/s10620-006-9178-1

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