Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β
Open accessAbstract
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) 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-α and IL-1β 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-α/IL-1β and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-α and IL-1β acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-α and IL-1β that inhibit GHR expression.
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TNF-a, IL-1b, and IL-6 induce hepatic growth hormone resistance in mice.
“In addition, TNF-a, IL-1b, and IL-6 induce hepatic growth hormone resistance in mice (Zhao et al, 2014).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Zhao et al, 2014
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- Authors
- Zhao, Y., Xiao, X., Frank, S. J., Lin, H. Y., & Xia, Y.
- Affiliations
- Chinese University of Hong Kong (HK)
- Children's Hospital of Chongqing Medical University (CN)
- University of Alabama at Birmingham (US)
- Harvard University (US)
- Corresponding author
- Xiao, Xiaoqiu
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2014-07-15
- Volume
- 307
- Issue
- 2
- Pages
- E186-E198
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC4101637
- OpenAlex
- W1985413489
- Cited by
- 56
- References
- 33
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 8 · 2019: 2 · 2018: 9 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Hong Kong
- Chinese University of Hong Kong
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK46395, R01DK058259, R01DK046395, R01DK071837, R-01 DK58259)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- interleukin-6, TNF-α, IL-1β, growth hormone receptor, insulin-like growth factor I, SOCS3, inflammatory cytokines, inflammation, liver, Huh7 cells, cytokine neutralization
- MeSH terms
- Animals, Cells, Cultured, Humans, Inflammation, Liver, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Receptors, Somatotropin, Growth Hormone, Tumor Necrosis Factor-alpha, Interleukin-6, Mice, Knockout, Neural Cell Adhesion Molecules, Mice, Interleukin-1beta
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