The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo

• Published in: Blood 2007-09, Vol.110 (5), p.1466-1474
• Main Authors: Boyle, Kristy, Egan, Paul, Rakar, Steven, Willson, Tracy A., Wicks, Ian P., Metcalf, Donald, Hilton, Douglas J., Nicola, Nicos A., Alexander, Warren S., Roberts, Andrew W., Robb, Lorraine
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Arthritis - genetics; Arthritis - metabolism; Arthritis - pathology; Bone Marrow - metabolism; Bone Marrow - pathology; Disease Models, Animal; Granulocyte Colony-Stimulating Factor - genetics; Granulocyte Colony-Stimulating Factor - metabolism; Hematopoiesis; Interleukin-6 - metabolism; Leukopoiesis - genetics; Mice; Mice, Mutant Strains; Receptors, Cytokine - metabolism; Signal Transduction - genetics; src Homology Domains - genetics; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-03-079178

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of granulocyte-colony stimulating factor (G-CSF) signaling in vivo. SOCS proteins regulate cytokine signaling by binding, via their SH2 domains, to activated cytokine receptors or their associated Janus kinases. In addition, they bind to the elongin B/C ubiquitin ligase complex via the SOCS box. To ascertain the contribution of the SOCS box of SOCS3 to in vivo regulation of G-CSF signaling, we generated mice expressing a truncated SOCS3 protein lacking the C-terminal SOCS box (SOCS3ΔSB/ΔSB). SOCS3ΔSB/ΔSB mice were viable, had normal steady-state hematopoiesis, and did not develop inflammatory disease. Despite the mild phenotype, STAT3 activation in response to G-CSF signaling was prolonged in SOCS3ΔSB/ΔSB bone marrow. SOCS3ΔSB/ΔSB bone marrow contained increased numbers of colony-forming cells responsive to G-CSF and IL-6. Treatment of the mice with pharmacologic doses of G-CSF, which mimics emergency granulopoiesis and therapeutic use of G-CSF, revealed that SOCS3ΔSB/ΔSB mice were hyperresponsive to G-CSF. Compared with wild-type mice, SOCS3ΔSB/ΔSB mice developed a more florid arthritis when tested using an acute disease model. Overall, the results establish a role for the SOCS box of SOCS3 in the in vivo regulation of G-CSF signaling and the response to inflammatory stimuli.