HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Malik, M. Articles by Ptasznik, A. Search for Related Content PubMed PubMed Citation Articles by Malik, M. Articles by Ptasznik, A.

Monocyte Migration and LFA-1-Mediated Attachment to Brain Microvascular Endothelia Is Regulated by SDF-1 through Lyn Kinase¹

Mobeen Malik^*, Ying-Yu Chen, Martha F. Kienzle^*, Brian E. Tomkowicz, Ronald G. Collman^2,* and Andrzej Ptasznik^2,

^* Division of Pulmonary, Allergy and Critical Care, and Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104

Infiltration of activated monocytes into the brain is a prerequisite for the development of various neurological disorders such as HIV-associated dementia, multiple sclerosis, and other inflammatory processes. In these pathologies, the chemokine SDF-1 (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1 stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for β₂ integrins. SDF-1 also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-, IL-1β, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-1. The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the β₂ integrin LFA-1 by SDF-1. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion to BMVEC through the LFA-1 integrin. These results provide a novel Lyn-mediated signaling mechanism for the regulation of monocyte movement at the blood-brain barrier.

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 R01MH61139 and P01NS27405 (to R.C.) and R01CA108552 (to A.P.).

² Address correspondence and reprint requests to Dr. Andrzej Ptasznik or Dr. Ronald G. Collman, University of Pennsylvania School of Medicine, 520 Johnson Pavilion, 36th and Hamilton Walk, Philadelphia, PA 19104. E-mail addresses: andrzej.ptasznik{at}comcast.net and collmanr{at}mail.med.upenn.edu

³ Abbreviations used in this paper: HAD, HIV-associated dementia; BMVEC, brain microvascular endothelial cell; BBB, blood-brain barrier; EBM, endothelial basal medium; siRNA, small interfering RNA; CNS, central nervous system; EC, endothelial cells; RFU, relative fluorescence units; PP2, pyrazolopirimidine.