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A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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Functional inactivation of CXC chemokine receptor 4-mediated responses through SOCS3 up-regulation

Silvia F Soriano1, Patricia Hernanz-Falcón, José Miguel Rodríguez-Frade

  • 1Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientifícas, Universidad Autónoma de Madrid, Campus de Cantoblanco, Spain.

The Journal of Experimental Medicine
|August 7, 2002
PubMed

Insights

Suppressors of cytokine signaling (SOCS) proteins, like SOCS3, can block chemokine responses. SOCS3 up-regulation impairs cell movement and calcium flux by interfering with JAK/STAT and Galpha(i) pathways, highlighting cytokine-chemokine signaling cross-talk.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Cytokines and chemokines are crucial for hematopoietic cell functions, including growth, differentiation, and migration.
  • Cytokine signaling involves Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to gene transcription, including SOCS proteins.
  • Chemokines also activate the JAK/STAT pathway via receptor dimerization.

Purpose of the Study:

  • To investigate the functional interaction between cytokine-induced SOCS3 and chemokine signaling pathways.
  • To determine if SOCS3 modulates cellular responses to chemokines like CXCL12.

Main Methods:

  • Assessing the impact of SOCS3 up-regulation on cellular responses to CXCL12, including calcium (Ca2+) flux and chemotaxis.
  • Investigating the molecular mechanisms by which SOCS3 affects chemokine signaling pathways (JAK/STAT, Galpha(i)).
  • Utilizing in vitro and in vivo models to evaluate the physiological relevance of these interactions.

Main Results:

  • SOCS3 overexpression or up-regulation, induced by cytokines like growth hormone, significantly impairs cellular responses to the chemokine CXCL12.
  • This impairment was observed in both Ca2+ flux and chemotaxis assays, in vitro and in vivo.
  • SOCS3 exerts its inhibitory effect by binding to the CXC chemokine receptor 4 (CXCR4), blocking JAK/STAT and Galpha(i) signaling pathways without affecting receptor expression.

Conclusions:

  • SOCS3 acts as a negative regulator of chemokine signaling, demonstrating a direct cross-talk between cytokine and chemokine pathways.
  • This cross-talk mechanism, mediated by SOCS3 binding to CXCR4, is critical for regulating immune cell responses.
  • Understanding this interaction provides insights into the coordinated regulation of the immune system.

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