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Publication Detail
Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Dragoni S, Hudson N, Kenny B-A, Burgoyne T, McKenzie JA, Gill Y, Blaber R, Futter CE, Adamson P, Greenwood J, Turowski P
  • Publication date:
  • Pagination:
    4074, 4085
  • Journal:
    Journal of immunology (Baltimore, Md. : 1950)
  • Volume:
  • Issue:
  • Medium:
  • Print ISSN:
  • Language:
  • Addresses:
    Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1-dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4+ lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1-induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.
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