IL-6, TNF- and IL-1 play distinct roles in inhibiting growth hormone signaling in the liver

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 632-648-Pediatric Growth Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-648
Yin Xia*1 and Yueshui Zhao2
1The Chinese University of Hong K, Hong Kong, 2The Chinese University of Hong Kong, Hong Kong, China
Growth failure is a major complication of childhood inflammatory diseases. Evidence suggests that during inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the anabolic gene IGF-I and the activation of catabolic processes. Decades of studies demonstrated that proinflammatory cytokines IL-6, TNF-α and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the exact mechanisms used by these individual cytokines to regulate GH signaling are not defined. Using postnatal mouse models of chronic and acute inflammation, we show that TNF-α and IL-1β but not IL-6 inhibited hepatic GH receptor (GHR) expression, and that IL-6 but not TNF-α and IL-1β stimulated expression of suppressor of cytokine signaling-3 (SOCS3). TNF-α/IL-1β and IL-6 acted primarily at GHR and SOCS3 respectively to inhibit the GH-IGF-I pathway. While TNF-α/IL-1β exerted a tonic inhibition on hepatic GH signaling, IL-6 activity is dependent on GHR expression. IL-6 inhibited GH signaling when GHR expression was high during initial inflammation, and it lost its ability to inhibit GH signaling when GHR expression was blocked by advanced inflammation. These results reveal previously undefined distinct mechanisms used by TNF-α/IL-1β and IL-6 to inhibit hepatic GH signaling, and previously unrecognized different roles of IL-6 in inhibiting GH signaling during initial and advanced inflammation. Our results may provide a new guidance for clinical practice in treating pediatric inflammation-induced GH resistance.

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