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 Blood, 1 September 2007, Vol. 110, No. 5, pp. 1466-1474.
Prepublished online as a Blood First Edition Paper on May 17, 2007; DOI 10.1182/blood-2007-03-079178.

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HEMATOPOIESIS

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

Kristy Boyle1,2, Paul Egan1, Steven Rakar3, Tracy A. Willson1, Ian P. Wicks1, Donald Metcalf1, Douglas J. Hilton1, Nicos A. Nicola1, Warren S. Alexander1, Andrew W. Roberts1, and Lorraine Robb1

1 The Walter and Eliza Hall Institute of Medical Research, Parkville; 2 Department of Medical Biology, University of Melbourne, Parkville; 3 Zenyth Therapeutics, Richmond, Australia

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 (SOCS3{Delta}SB/{Delta}SB). SOCS3{Delta}SB/{Delta}SB 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 SOCS3{Delta}SB/{Delta}SB bone marrow. SOCS3{Delta}SB/{Delta}SB 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 SOCS3{Delta}SB/{Delta}SB mice were hyperresponsive to G-CSF. Compared with wild-type mice, SOCS3{Delta}SB/{Delta}SB 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.


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Related Article in Blood Online:

SOCS box: fine-tuning inflammatory responses
Robert P. Coppes
Blood 2007 110: 1403-1404. [Full Text] [PDF]





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