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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607420

Received for publication June 20, 2007.
Revised October 16, 2007.
Accepted for publication November 5, 2007.

Article

Stromal cell-derived factor 1-{alpha} (SDF)-induced human T cell chemotaxis becomes phosphoinositide 3-kinase (PI3K)-independent: role of PKC-{theta}

Nahid A. Shahabi , K. McAllen , and Burt M. Sharp @

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee, USA

@ To whom correspondence should be addressed. E-mail: bsharp{at}utmem.edu.


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Abstract

Stromal cell-derived factor 1{alpha} (SDF-1{alpha}) is the exclusive ligand for the chemokine receptor CXCR4. This receptor plays a pivotal role in immune responses, the pathogenesis of infection such as HIV, and cellular trafficking. However, the signaling mechanisms regulating SDF-driven T cell migration are not well defined. In this study, we determined the role of PI3K and protein kinase C- {theta} (PKC-{theta}) in SDF-induced human T cell migration in fresh versus cultured T cells. Purified h-T cells (fresh vs. 48 h in media, unstimulated or activated by anti-CD3+anti-CD28) were used. Western blots showed that SDF induced phospho-(p)-Akt [threonine (Thr)308 and serine 473], a proxy for PI3K activity, in fresh cells and p-PKC-{theta} in 48 h unstimulated cells. LY294002 (PI3K inhibitor) reduced SDF-induced chemotaxis in fresh cells by 51%, whereas it minimally affected chemotaxis in 48 h unstimulated or activated cells. However, a specific PKC-{theta} inhibitor, pseudosubstrate for PKC-{theta}, reduced chemotaxis in 48 h unstimulated and stimulated T cells by 72% and 87%, respectively. Thus, chemotaxis becomes independent of PI3K signaling in human T cells cultured for 48 h. Under these conditions, PKC-{theta} is phosphorylated (Thr538) by SDF, and chemotaxis becomes largely PKC-{theta}-dependent.

Key Words: Akt • LY294002 • pseudosubstrate • CXCR4




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