SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine.
Mice lacking suppressor of cytokine signaling-1 (SOCS1) develop a complex fatal neonatal disease. In this study, SOCS1-/- mice were shown to exhibit excessive responses typical of those induced by interferon gamma (IFNgamma), were hyperresponsive to viral infection, and yielded macrophages with an enhanced IFNgamma-dependent capacity to kill L. major parasites. The complex disease in SOCS1-/- mice was prevented by administration of anti-IFNgamma antibodies and did not occur in SOCS1-/- mice also lacking the IFNgamma gene. Although IFNgamma is essential for resistance to a variety of infections, the potential toxic action of IFNgamma, particularly in neonatal mice, appears to require regulation. Our data indicate that SOCS1 is a key modulator of IFNgamma action, allowing the protective effects of this cytokine to occur without the risk of associated pathological responses.
Alexander
W S
WS
The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
Starr
R
R
Fenner
J E
JE
Scott
C L
CL
Handman
E
E
Sprigg
N S
NS
Corbin
J E
JE
Cornish
A L
AL
Darwiche
R
R
Owczarek
C M
CM
Kay
T W
TW
Nicola
N A
NA
Hertzog
P J
PJ
Metcalf
D
D
Hilton
D J
DJ
D018354:Alphavirus Infections / Q000401:mortality / Q000517:prevention & control; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004198:Disease Susceptibility; D018507:Gene Expression Regulation, Developmental; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D018320:Leishmania major / Q000276:immunology; D007896:Leishmaniasis / Q000401:mortality / Q000517:prevention & control; D008231:Lymphopenia / Q000401:mortality / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012097:Repressor Proteins; D012672:Semliki forest virus / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
D002352:Carrier Proteins; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma