Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis

• Main Authors: Christoffer Soendergaard, Peter Helding Kvist, Peter Thygesen, Mats Reslow, Ole Haagen Nielsen, John Joseph Kopchick, Thomas Lindebo Holm
• Format: Article
• Language: English
• Published: MDPI AG 2017-09-01
• Series: International Journal of Molecular Sciences
• Subjects: experimental colitis; GH resistance; GHR; IGF-1; inflammation; long acting human GH; ulcerative colitis
• Online Access: https://www.mdpi.com/1422-0067/18/10/2046

Growth hormone (GH) resistance may develop as a consequence of inflammation during conditions such as inflammatory bowel disease, encompassing ulcerative colitis (UC). However, the specific role of the GH–insulin growth factor (IGF)-1-axis and/or the functional consequences of GH resistance in this condition are unclear. In situ hybridization targeting the GH receptor (GHR) and relevant transcriptional analyses were performed in patients with UC and in IL-10 knock-out mice with piroxicam accelerated colitis (PAC). Using cultured primary epithelial cells, the effects of inflammation on the molecular mechanisms governing GH resistance was verified. Also, the therapeutic potential of GH on mucosal healing was tested in the PAC model. Inflammation induced intestinal GH resistance in UC and experimental colitis by down-regulating GHR expression and up-regulating suppressor of cytokine signalling (SOCS) proteins. These effects are driven by pro-inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) as confirmed using primary epithelial cells. Treatment of experimental colitis with GH increased IGF-1 and body weight of the mice, but had no effects on colonic inflammation or mucosal healing. The high transcriptional similarity between UC and experimental colitis accentuates the formation of intestinal GH resistance during inflammation. Inflammation-induced GH resistance not only impairs general growth but induces a state of local resistance, which potentially impairs the actions of GH on mucosal healing during colitis when using long-acting GH therapy.