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Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-?, and IL-1?.

ABSTRACT: During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-?, and IL-1? are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-?, and IL-1? to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-? and IL-1? inhibited GH receptor (GHR) expression but had minor effects on the downstream suppressor of cytokine signaling (SOCS)3, while IL-6 induced SOCS3 expression but had no effect on GHR expression in Huh-7 cells. Consistent with the in vitro observations, neutralization of TNF-? and IL-1? in mouse models of inflammation did not significantly alter SOCS3 expression stimulated by inflammation but restored GHR and IGF-I expression suppressed by inflammation. Neutralization of IL-6 did not alter inflammation-suppressed GHR expression but drastically reduced the inflammation-stimulated SOCS3 expression and restored IGF-I expression. Interestingly, when the GH-IGF-I pathway was turned off by maximal inhibition of GHR expression, IL-6 and SOCS3 were no longer able to regulate IGF-I expression. Taken together, our results suggest that TNF-?/IL-1? and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-? and IL-1? acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-? and IL-1? that inhibit GHR expression.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC4101637 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β.

Zhao Yueshui Y Xiao Xiaoqiu X Frank Stuart J SJ Lin Herbert Y HY Xia Yin Y

American journal of physiology. Endocrinology and metabolism 20140603 2

During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-α, and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-α, and IL-1β to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-α and IL-1β inhibited GH receptor (GHR) e ...[more]

PMID: 24895283

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Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-?, and IL-1?.

Publications

Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β.

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