| First Author | Zhao Y | Year | 2014 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 307 |
| Issue | 2 | Pages | E186-98 |
| PubMed ID | 24895283 | Mgi Jnum | J:215330 |
| Mgi Id | MGI:5605124 | Doi | 10.1152/ajpendo.00652.2013 |
| Citation | Zhao Y, et al. (2014) Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-alpha, and IL-1beta. Am J Physiol Endocrinol Metab 307(2):E186-98 |
| abstractText | 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-alpha, and IL-1beta are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-alpha, and IL-1beta to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-alpha and IL-1beta 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-alpha and IL-1beta 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-alpha/IL-1beta and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-alpha and IL-1beta acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-alpha and IL-1beta that inhibit GHR expression. |
