The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published online 29 July 2002 doi:10.1084/jem.20012041
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© Rockefeller University Press, 0022-1007/2002/8/311/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 3, August 5, 2002 311-321
Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulation

Silvia F. Soriano, Patricia Hernanz-Falcón, José Miguel Rodríguez-Frade, Ana Martín de Ana, Ruth Garzón, Carla Carvalho-Pinto, Antonio J. Vila-Coro, Angel Zaballos, Dimitrios Balomenos, Carlos Martínez-A. and Mario Mellado

Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientifícas, Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain

Address correspondence to Carlos Martínez-A., Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain. Phone: 34-91-585-4660; Fax: 34-91-372-0493; E-mail: cmartineza{at}cnb.uam.es

Hematopoietic cell growth, differentiation, and chemotactic responses require coordinated action between cytokines and chemokines. Cytokines promote receptor oligomerization, followed by Janus kinase (JAK) kinase activation, signal transducers and transactivators of transcription (STAT) nuclear translocation, and transcription of cytokine-responsive genes. These include genes that encode a family of negative regulators of cytokine signaling, the suppressors of cytokine signaling (SOCS) proteins. After binding their specific receptors, chemokines trigger receptor dimerization and activate the JAK/STAT pathway. We show that SOCS3 overexpression or up-regulation, stimulated by a cytokine such as growth hormone, impairs the response to CXCL12, measured by Ca2+ flux and chemotaxis in vitro and in vivo. This effect is mediated by SOCS3 binding to the CXC chemokine receptor 4 receptor, blocking JAK/STAT and G{alpha}i pathways, without interfering with cell surface chemokine receptor expression. The data provide clear evidence for signaling cross-talk between cytokine and chemokine responses in building a functional immune system.

Key Words: SOCS3 • JAK-STAT activation • chemokine signaling • cytokine signaling


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