Abstract | BACKGROUND/AIMS: Preservation of function requires tight regulation of the cellular events initiated when hepatic ischemia is followed by reperfusion (IR). One important mechanism modulating the cytokine-directed response to injury is Suppressors of Cytokine Signaling. SOCS1 and SOCS3 ensure appropriate intensity and duration of cytokine signaling through negative feedback on JAK-STAT signaling. The contribution of SOCS1 and SOCS3-mediated regulation to the evolution of hepatic IR injury is unknown. METHODS: C57Blk6 mice were subjected to mild (20 min) or severe (90 min) hepatic ischemia. Liver was analyzed for cytokine and SOCS1/3 induction as well as JAK-STAT activation at intervals after reperfusion. RESULTS: Tnf, Il-1beta, and Il-6 expression paralleled increasing injury severity. Despite early phosphorylation of both STAT1 and STAT3 after severe injury, only nuclear translocation of activated STAT3, suggesting that the induction of target genes through JAK-STAT after IR is predominantly via STAT3. Socs3 was expressed across the injury spectrum while Socs1 was induced only in the face of severe IR injury. Severe IR in Il-6 deficient mice confirmed that Il-6, acting via STAT3, serves as a primary inducer of both regulatory mechanisms. CONCLUSIONS: Under the influence of IL-6-mediated STAT3 signaling, Socs1 serves as a complimentary regulatory mechanism when Socs3 is insufficient to limit cytokine-mediated inflammation after hepatic IR.
|
Authors | Lorrie A Langdale, Vicki Hoagland, Whitney Benz, Kimberly J Riehle, Jean S Campbell, Denny H Liggitt, Nelson Fausto |
Journal | Journal of hepatology
(J Hepatol)
Vol. 49
Issue 2
Pg. 198-206
(Aug 2008)
ISSN: 0168-8278 [Print] Netherlands |
PMID | 18471922
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
|
Chemical References |
- Interleukin-1beta
- Interleukin-6
- STAT1 Transcription Factor
- STAT3 Transcription Factor
- Socs1 protein, mouse
- Socs3 protein, mouse
- Stat1 protein, mouse
- Stat3 protein, mouse
- Suppressor of Cytokine Signaling 1 Protein
- Suppressor of Cytokine Signaling 3 Protein
- Suppressor of Cytokine Signaling Proteins
- Tumor Necrosis Factor-alpha
|
Topics |
- Animals
- Gene Expression Profiling
- Interleukin-1beta
(genetics, metabolism)
- Interleukin-6
(genetics, metabolism)
- Liver
(immunology, metabolism, pathology)
- Liver Diseases
(immunology, metabolism, pathology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Reperfusion Injury
(immunology, metabolism, pathology)
- STAT1 Transcription Factor
(metabolism)
- STAT3 Transcription Factor
(metabolism)
- Severity of Illness Index
- Signal Transduction
(immunology)
- Suppressor of Cytokine Signaling 1 Protein
- Suppressor of Cytokine Signaling 3 Protein
- Suppressor of Cytokine Signaling Proteins
(metabolism)
- Tumor Necrosis Factor-alpha
(genetics, metabolism)
|