Hepatic growth hormone resistance during sepsis is associated with increased suppressors of cytokine signaling expression and impaired growth hormone signaling.
OBJECTIVE
During sepsis, a two- to four-fold increase in circulating growth hormone (GH) is seen with 40-50% reductions in plasma insulin-like growth factor (IGF)-I. The suppressors of cytokine signaling (SOCS), inhibitors of cytokine, and growth factor signaling via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have been implicated in the development of hepatic GH resistance. In this study we examine the effects of sepsis on GH-induced IGF-I expression and potential mechanisms for GH resistance.


METHODS
Prospective experimental study.


METHODS
University research laboratory.


METHODS
Male Sprague-Dawley rats.


METHODS
Rats were randomized to laparotomy alone (control) or implantation of fecal agar pellets inoculated with Escherichia coli and Bacteroides fragilis (sepsis). GH was injected intravenously to assess hepatic IGF-I synthesis and GH signaling.


RESULTS
Plasma IGF-I was measured in both groups at baseline (4 hrs postoperatively) and then again at 12 hrs and 24 hrs after GH administration. Basal IGF-I levels were similar in both groups, but controls had a 35% increase in IGF-I at 12 hrs, whereas septic rats demonstrated reductions in circulating IGF-I at 12 and 24 hrs after GH. Hepatic expression of SOCS-1, -2, -3, and cytokine-inducible SH2-containing protein (CIS) were determined at 1, 4, 8, and 24 hrs in septic and control rats by Northern blot. SOCS-1, SOCS-3, and CIS messenger RNA in liver were increased from 4 to 8 hrs after the induction of sepsis (p < .05 for SOCS-1 and -3). Total GH receptor (GHR), JAK2, and STAT5 signaling proteins and the time course of STAT5 activation were also measured in liver after recombinant human GH administration by immunoblot and electrophoretic mobility shift analysis. Levels of total GHR, JAK2, and STAT5 were unaltered in liver from septic rats. However, phosphorylated STAT5 and STAT5 DNA binding were significantly reduced 30 mins after GH administration in liver from septic rats.


CONCLUSIONS
Sepsis diminished STAT5 phosphorylation and activity in liver as well as plasma IGF-I following GH administration. Hepatic messenger RNA expression of SOCS-1, SOCS-3, and CIS was transiently increased during abdominal sepsis and temporally associated with the development of hepatic GH resistance.
Departments of Surgery, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
Gladys
G
Yumet
Margaret L
ML
Shumate
D Patrick
DP
Bryant
Charles H
CH
Lang
Robert N
RN
Cooney
D000704:Analysis of Variance; D000818:Animals; D013006:Growth Hormone / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D053614:Janus Kinase 2; D008099:Liver / Q000378:metabolism*; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000097:blood; D011518:Proto-Oncogene Proteins / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000097:blood; D018805:Sepsis / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2