生長滯後是包括炎症性腸病在內的炎症疾病引起的併發症。實驗表明，炎症使肝臟對生長激素(GH)的作用變得不敏感或引起生長激素抵抗。生長激素抵抗會引起胰島素生長因子-1 (IGF-I)的表達下降，並且會啟動一系列的代謝反應。多年來的研究證明炎症因子白介素-6 (IL-6)，腫瘤壞死因子 -α (TNF-α)和白介素-1β(IL-1β)參與肝臟生長激素抵抗的病理過程。然而這些炎症因子調控生長激素通路的具體機理尚不清楚。通過用人肝癌細胞系Huh-7和慢性炎症及急性炎症兩種老鼠模型，我們發現: 1) TNF-α和IL-1β抑制生長激素受體(GHR)的表達; 2) IL-6誘導細胞因子信號轉導抑制因子-3 (SOCS3)的高表達; 3) IL-6-SOCS3途徑對GH-IGF-I信號通路的抑制作用依賴于GHR的表達量，當TNF-α及IL-1β升高而使GHR的表達量下降後，IL-6就不再對GH-IGF-I信號通路有抑制作用。以上結果表明IL-6， TNF-α和IL-1β抑制肝臟生長激素信號通路的機制是不一樣的，這些結果或許對臨床上治療青少年中炎症引起的生長激素抵抗疾病有一定的指導意義。 / 成纖維細胞生長因子(FGF) 通過結合和啟動成纖維細胞生長因子受體(FGFR)而參與許多生理過程。FGF19屬於FGF15/19亞家族，這個亞家族還包括FGF21和FGF23。FGF19調節肝臟中膽汁酸的穩態及蛋白和糖原的合成。FGF19通過與FGFR4及共受體β-klotho結合來啟動信號通路。研究表明，TNF-α通過抑制共受體β-klotho的表達來抑制脂肪細胞中的FGF21信號通路。然而IL-6，TNF-α和IL-1β在調節肝臟FGF19信號通路中的作用尚不清楚。我們的體外細胞和體內動物實驗結果表明，IL-1β通過JNK和NF-κB通路抑制肝臟中β-klotho的表達。IL-6與TNF-α不調節Huh-7細胞中β-klotho的表達。 / 綜上所述，IL-6，TNF-α及IL-1β在肝臟生長激素及FGF19通路中起不同的調節作用。 / Growth failure is a major complication of inflammatory diseases including inflammatory bowel disease. 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 pro-inflammatory cytokines IL-6, TNF-α and IL-1β are 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 Huh-7 human hepatoma cells and 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 the active GH pathway. IL-6 lost its inhibition on the GH-IGF-I pathway when GHR expression was blocked as the inflammation progressed. These results reveal previously undefined distinct mechanisms used by TNF-α/IL-1β and IL-6 to inhibit the hepatic GH pathway. Our results may provide a new guidance for clinical practice in treating pediatric infammation-induced GH resistance. / Fibroblast growth factors (FGFs) play critical roles in many physiological processes by binding to and activating FGF receptor (FGFR) family. FGF19 belongs to FGF15/19 subfamily of FGFs that includes FGF15/19, FGF21 and FGF23. FGF19 has been shown to regulate bile acid homeostasis, and protein and glycogen synthesis in the liver. FGF19 binds FGFR4 and the co-receptor β-klotho to initiate signaling. Studies have shown that proinflammatory cytokines such as TNF-α can impair FGF21 signaling in adipose cells by repressing the expression of β-klotho. However, little is known about the effects of IL-6, TNF-α and IL-1β on regulating hepatic FGF19 signaling. In the present study, we found that IL-1β inhibited β-klotho expression both in vitro and in vivo, and this inhibition required JNK and NF-κB pathways. IL-6 and TNF-α did not inhibit β-klotho expression in Huh-7 cells. / Taken together, our results demonstrate that IL-6, TNF-α and IL-1β play different roles in regulating the GH and FGF-19 pathways in the liver. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhao, Yueshui. / Thesis (Ph.D.) Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 147-182). / Abstracts also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_1077709 |
| Date | January 2013 |
| Contributors | Zhao, Yueshui (author.), Xia, Yin , active 2014 (thesis advisor.), Chinese University of Hong Kong Graduate School. Division of Biomedical Sciences, (degree granting institution.) |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography, text |
| Format | electronic resource, electronic resource, remote, 1 online resource (xxi, 182 leaves) : illustrations (some color), computer, online resource |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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