Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis

Abstract

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.

COX-2–PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis

“…Intestinal biopsies were obtained form an independent patient cohort at Herlev Hospital consisting of healthy control subjects and UC patients with varying disease activity based on the Mayo score [ 23 ]. Two neighboring biopsies from inflamed sigmoid colon were obtained from each patient within a 5 cm radius, from which RNA was obtained and analyzed by microarray as previously described [ 28 ]. In addition, we analyzed ANXA1 expression from Affymetrix microarray data downloaded from the Gene Expression Omnibus website ( www.ncbi.nlm.nih.gov/geo/ ) and extracted data from the GSE14580 study [ 29 ].…”

Signal Transduction for TNFα-Induced Type II SOCS Expression and Its Functional Implication in Growth Hormone Resistance in Carp Hepatocytes

“…In fish models including rainbow trout (64), catfish (58), and common carp (61,62), TNFα expression induced by LPS has been reported, e.g., in macrophages and leucocytes, but the functional relevance of the phenomenon in GH resistance has not been examined. In mammals, endotoxin exposure can induce GH resistance at tissue level, e.g., in the liver, muscle and intestine (3,4,68). The effect is mediated by local production of cytokines including TNFα, IL-1β, and IL-6 (5,68), which are known to reduce GH responsiveness by reducing GHR expression (10,11) or blocking GHR signaling via SOCS expression (3,13).…”

“…In mammals, endotoxin exposure can induce GH resistance at tissue level, e.g., in the liver, muscle and intestine (3,4,68). The effect is mediated by local production of cytokines including TNFα, IL-1β, and IL-6 (5,68), which are known to reduce GH responsiveness by reducing GHR expression (10,11) or blocking GHR signaling via SOCS expression (3,13). Apparently, different cytokines have their distinct role in GH resistance induced by endotoxin (33).…”

Inhibitory Role of Growth Hormone in the Induction and Progression Phases of Collagen-Induced Arthritis

“…Recombinant human GH improves survival and protects against acute lung injury in murine Staphylococcus aureus sepsis ( 66 ) and protects from acute pancreatitis ( 67 ). GH decreases gut inflammation and improves or maintains gut barrier function, which ultimately inhibits development of inflammatory bowel disease ( 14 , 68 ); co-administration of epidermal growth factor and GH-releasing peptide-6, a GH secretagogue, improves clinical recovery in experimental autoimmune encephalitis ( 69 ). GH is thus a candidate for potential treatment of inflammatory disorders and therapy for arthritis and other autoimmune diseases.…”