Signal Transduction for TNF?-Induced Type II SOCS Expression and Its Functional Implication in Growth Hormone Resistance in Carp Hepatocytes.

ABSTRACT: In mammals, local production of tumor necrosis factor ? (TNF?) inhibits growth hormone (GH)-induced IGF-I expression at tissue level and contributes to GH resistance caused by sepsis/endotoxemia and inflammation. Although the loss of GH responsiveness can be mediated by a parallel rise in SOCS expression, the signaling mechanisms for TNF?-induced SOCS expression at the hepatic level have not been characterized and the comparative aspects of the phenomenon, especially in lower vertebrates, are still unknown. Recently, type II SOCS, including SOCS1-3 and CISH, have been cloned in grass carp and shown to act as the feedback repressors for GH signaling via JAK2/STAT5 pathway. To shed light on the mechanisms for TNF?-induced GH resistance in fish model, grass carp TNF? was cloned and confirmed to be a single-copy gene expressed in various tissues including the liver. In carp hepatocytes, incubation with the endotoxin LPS induced TNF? expression with parallel rises in SOCS1-3 and CISH mRNA levels. Similar to LPS, TNF? treatment could block GH-induced IGF-I/-II mRNA expression and elevate SOCS1, SOCS3, and CISH transcript levels. However, TNF? was not effective in altering SOCS2 expression. In parallel experiment, LPS blockade of IGF-I/-II signals caused by GH could be partially reverted by TNF? receptor antagonism. At hepatocyte level, TNF? induction also triggered rapid phosphorylation of I?B?, MEK1/2, ERK1/2, MKK3/6, P38 MAPK, Akt, JAK2, and STAT1,3,5, and TNF?-induced SOCS1, SOCS3, and CISH mRNA expression could be negated by inhibiting the IKK/NF?B, MAPK, PI3K/Akt, and JAK/STAT cascades. Our findings, as a whole, suggest that local production of TNF? may interfere with IGF-I/-II induction by GH in the carp liver by up-regulation of SOCS1, SOCS3, and CISH via IKK/NF?B, MAPK, PI3K/Akt, and JAK/STAT-dependent mechanisms, which may contribute to GH resistance induced by endotoxin in carp species.

SUBMITTER: Jiang X 

PROVIDER: S-EPMC7003395 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature