SOCS-1 is a central mediator of steroid-increased thymocyte apoptosis and decreased survival following sepsis.
Suppressor of Cytokine Signaling (SOCS) proteins are recently identified inhibitors/regulators of cytokine/growth factor signaling pathways. We have previously shown that SOCS-3 is upregulated in mice after sepsis induced by cecal ligation and puncture; however, the contribution of SOCS-1 to septic morbidity and mortality is unclear. In the present study, we characterized SOCS-1 expression in different tissues and delineated putative mechanisms effecting SOCS-1 expression in thymus from septic mice. We observed no difference in SOCS-1 expression in blood, peritoneal leukocytes, lung, and spleen taken from sham or septic animals at 24 h after surgery. In contrast, SOCS-1 expression in thymus declined significantly after sepsis and this down-regulation of SOCS-1 was associated with increased thymocyte apoptosis as well as augmented Bax recruitment to the mitochondria. Administration of RU-38486, a steroid receptor antagonist, reversed the above effects in the septic thymus. Furthermore, SOCS-1+/- mice showed a significant higher mortality when compared to SOCS-1+/+ mice after sepsis. Together, these results show that sepsis increases steroid-induced thymic lymphoid cell apoptosis, which is associated with reduced SOCS-1 expression and increased Bax translocation to mitochondria. Survival data suggests that SOCS-1 protein may play an important role in sepsis.
Chung
Chun-Shiang
CS
Division of Surgical Research, Department of surgery, Aldrich 227, Brown University School Medicine/Rhode Island Hospital, Providence, RI 02903, USA. aayala@lifespan.org
Chen
Yaping
Y
Grutkoski
Patricia S
PS
Doughty
Lesley
L
Ayala
Alfred
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015735:Mifepristone / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D015398:Signal Transduction; D013256:Steroids / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C491590:Socs1 protein, mouse; D013256:Steroids; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051028:bcl-2-Associated X Protein; D015735:Mifepristone; D003907:Dexamethasone; C505409:Casp3 protein, mouse; D053148:Caspase 3