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Cyclin-Dependent Kinase Inhibitors Block Leukocyte Adhesion and Migration¹

Li Liu^2,*, Barbara Schwartz^2,*, Yoshiaki Tsubota, Elaine Raines, Hiroaki Kiyokawa, Karyn Yonekawa^*, John M. Harlan^3,4,* and Lynn M. Schnapp^3,4,

^* Division of Hematology, Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Pathology, University of Washington, Seattle, WA 98104; and Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Leukocyte trafficking is a tightly regulated process essential for an appropriate inflammatory response. We now report a new adhesion pathway that allows unstimulated leukocytes to adhere to and migrate through exposed endothelial matrix or high-density ligand, a process we have termed ligand-induced adhesion. This ligand-induced adhesion is integrin mediated, but in contrast to phorbol ester-stimulated adhesion, it is not dependent on the small GTPase Rap-1 activity. Instead, we show a critical role for cyclin-dependent kinase (Cdk) 4 in ligand-induced adhesion by three independent lines of evidence: inhibition by pharmacological inhibitors of Cdk, inhibition by dominant-negative construct of Cdk4, and inhibition by Cdk4 small interfering RNA. The major substrate of Cdk4, Rb, is not required for ligand-induced adhesion, suggesting the involvement of a novel Cdk4 substrate. We also demonstrate that Cdk4^–/– mice have impaired recruitment of lymphocytes to the lung following injury. The finding that Cdk inhibitors can block leukocyte adhesion and migration may expand the clinical indications for this emerging class of therapeutics.

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 Grants HL18645 (to J.M.H. and E.W.R.), HL067267 (to E.W.R.), and HL HL083481 and American Lung Association Career Investigator Award (to L.M.S.).

² L.L. and B.S. contributed equally to this work.

³ J.M.H. and L.M.S. shared senior authorship.

⁴ Address correspondence and reprint requests to Dr. Lynn M. Schnapp or Dr. John M. Harlan, Box 359640, 325 9th Avenue, Seattle, WA 98104. E-mail addresses: lschnapp{at}u.washington.edu and jharlan{at}u.washington.edu

⁵ Abbreviations used in this paper: Cdk, cyclin-dependent kinase; BAEC, bovine aortic endothelial cell; EC, endothelial cell; siRNA, small interfering RNA; BALF, bronchoalveolar lavage fluid; Rb, retinoblastoma; DN, dominant negative; PDBu, phorbol dibutyrate.