title: Functional inactivation of CXC chemokine receptor 4-mediated responses through SOCS3 up-regulation.
abstract: 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 Ca(2+) 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 Galpha(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.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientifícas, Universidad Autónoma de Madrid, Campus de Cantoblanco, Spain.
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Soriano
authors.forename: Patricia
authors.initials: P
authors.lastname: Hernanz-Falcón
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Rodríguez-Frade
authors.forename: Ana Martín
authors.initials: AM
authors.lastname: De Ana
authors.forename: Ruth
authors.initials: R
authors.lastname: Garzón
authors.forename: Carla
authors.initials: C
authors.lastname: Carvalho-Pinto
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Vila-Coro
authors.forename: Angel
authors.initials: A
authors.lastname: Zaballos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Balomenos
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D013006:Growth Hormone / Q000494:pharmacology; D006801:Humans; D053613:Janus Kinase 1; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D011506:Proteins; D019718:Receptors, CXCR4; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D002118:Calcium