Functional inactivation of CXC chemokine receptor 4-mediated responses through SOCS3 up-regulation.
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.
Soriano
Silvia F
SF
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientifícas, Universidad Autónoma de Madrid, Campus de Cantoblanco, Spain.
Hernanz-Falcón
Patricia
P
Rodríguez-Frade
José Miguel
JM
De Ana
Ana Martín
AM
Garzón
Ruth
R
Carvalho-Pinto
Carla
C
Vila-Coro
Antonio J
AJ
Zaballos
Angel
A
Balomenos
Dimitrios
D
Martínez-A
Carlos
C
Mellado
Mario
M
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
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