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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1403-1404.
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HEMATOPOIESIS
Comment on Boyle et al, page 1466
SOCS box: fine-tuning inflammatory responses
Robert P. Coppes
UNIVERSITY OF GRONINGEN
Suppressor of cytokine signaling 3 (SOCS3) protein regulates the response of bone marrow cells to granulocyte colony-stimulating factor (G-CSF). Boyle and colleagues report involvement of the SOCS3 box of SOCS3 in the in vivo regulation of inflammatory responses.
Blood cell production and mobilization, which are tightly regulated by hematopoietic growth factors and cytokines, are negatively influenced by suppressor of cytokine signaling (SOCS) proteins. SOCS proteins regulate cytokine receptor turnover.1 One of these, the SOCS3 protein, is a major physiological regulator of G-CSF signaling. It contains a central SH2 domain, which recognizes the activated G-CSF receptor, and a highly conserved C-terminal region, the so-called SOCS3 box, which recruits E3 ligase activity leading to ubiquitination and degradation of the receptor.2 To elucidate the physiological role of the SOCS3 box of SOCS3 in the regulation of G-CSF signaling and response to inflammatory stimuli, Boyle and colleagues generated mice with a deletion of only the SOCS3 box. Unlike a full knockout of the SOCS3 gene that results in embryonic lethality3 and deletion of SOCS3 specifically in hematopoietic cells, which leads to severe inflammatory disease4 under normal conditions, deletion only of the SOCS3 box resulted in a slight neutrophilia. However, in response to G-CSF, an increased transcription and prolonged activation of STAT3, which is required for the induction of SOCS3 in response to G-CSF, was observed in primary bone marrow cells (BMCs) of SOCS3-box–deleted mice compared with wild-type BMCs. Moreover, SOCS3-box–negative BMCs were hyperresponsive to G-CSF, which led to increased BMC proliferation and mobilization and granulopoiesis. Interestingly, a more fulminant arthritis was also observed in SOCS3-box–deleted mice after IL-1 injection. Because this model is dependent on G-CSF, this response is probably due to exaggerated G-CSF responsiveness.
The data show that the SOCS3 box of SOCS3 plays a physiologically important modulatory role in G-CSF–induced BMC responses, most likely due to a retarded G-CSF receptor breakdown.1
Because the normally low levels of G-CSF are up-regulated after infection, a potentially therapeutic role may be possible for the use SOCS3 proteins. Gene delivery of whole SOCS3 has already been shown to protect against lethal endotoxic shock,5 tempering inflammatory responses in mice. Although difficult to achieve, specific targeting of this SOCS3 box may allow more subtle modulation of inflammatory responses. Moreover, modulation of SOCS boxes of the SOCS protein family may be useful in studying the regulation of other cytokine-receptor signaling pathways. Therefore, this and future studies may be of aid in designing specific SOCS-box–related therapies that may be effective in autoimmune and other inflammation-related diseases.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Irandoust MI, Aarts LH, Roovers O, et al. Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor. EMBO J 2007; 26:1782–1793.[CrossRef][Medline]
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- Kile BT, Schulman BA, Alexander WS, et al. The SOCS box: a tale of destruction and degradation. Trends Biochem Sci 2002; 27:235–241.[CrossRef][Medline]
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- Roberts AW, Robb L, Rakar S, et al. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc Natl Acad Sci U S A 2001; 98:9324–9329.[Abstract/Free Full Text]
- Croker BA, Metcalf D, Robb L, et al. SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity 2004; 20:153–165.[CrossRef][Medline]
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- Fang M, Dai H, Yu G, Gong F. Gene delivery of SOCS3 protects mice from lethal endotoxic shock. Cell Mol Immunol 2005; 2:373–377.[Medline]
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The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo
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