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VCAM-1 Signals Activate Endothelial Cell Protein Kinase C via Oxidation¹

Allergy-Immunology Division, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Lymphocyte binding to VCAM-1 activates endothelial cell NADPH oxidase, resulting in the generation of 1 µM H₂O₂. This is required for VCAM-1-dependent lymphocyte migration. In this study, we identified a role for protein kinase C (PKC) in VCAM-1 signal transduction in human and mouse endothelial cells. VCAM-1-dependent spleen cell migration under 2 dynes/cm² laminar flow was blocked by pretreatment of endothelial cells with dominant-negative PKC or the PKC inhibitors, Rö-32-0432 or Gö-6976. Phosphorylation of PKC^Thr638, an autophosphorylation site indicating enzyme activity, was increased by Ab cross-linking of VCAM-1 on endothelial cells or by the exogenous addition of 1 µM H₂O₂. The anti-VCAM-1-stimulated phosphorylation of PKC^Thr638 was blocked by scavenging of H₂O₂ and by inhibition of NADPH oxidase. Furthermore, anti-VCAM-1 signaling induced the oxidation of endothelial cell PKC. Oxidized PKC is a transiently active form of PKC that is diacylglycerol independent. This oxidation was blocked by inhibition of NADPH oxidase. In summary, VCAM-1 activation of endothelial cell NADPH oxidase induces transient PKC activation that is necessary for VCAM-1-dependent transendothelial cell migration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant RO1 HL68171 (to J.M.C.-M.).

² Address correspondence and reprint requests to Dr. Joan M. Cook-Mills, Allergy-Immunology Division, Feinberg School of Medicine, Northwestern University, McGaw-304, 240 East Huron, Chicago, IL 60611. E-mail address: j-cook-mills{at}northwestern.edu

³ Abbreviations used in this paper: ROS, reactive oxygen species; PKC, protein kinase C; DAG, diacylglycerol; HMEC-L, human microvascular endothelial cells from the lung; DPI, diphenyleneiodonium chloride; IAF, iodoacetamidofluorescein; DN, dominant negative; MMP, matrix metalloproteinase; PP, phosphatase.

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