The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo.
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.
Boyle
Kristy
K
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Egan
Paul
P
Rakar
Steven
S
Willson
Tracy A
TA
Wicks
Ian P
IP
Metcalf
Donald
D
Hilton
Douglas J
DJ
Nicola
Nicos A
NA
Alexander
Warren S
WS
Roberts
Andrew W
AW
Robb
Lorraine
L
D000208:Acute Disease; D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D019891:Leukopoiesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D018121:Receptors, Cytokine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains / Q000235:genetics
D015850:Interleukin-6; D018121:Receptors, Cytokine; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016179:Granulocyte Colony-Stimulating Factor