Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo
CB#7545, Dept. of Cell and Molecular Physiology, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545, USA.AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 10/2006; 291(3):G472-81. DOI: 10.1152/ajpgi.00218.2005
Suppressors of cytokine signaling (SOCS) typically limit cytokine receptor signaling via the JAK-STAT pathway. Considerable evidence demonstrates that SOCS2 limits growth hormone (GH) action on body and organ growth. Biochemical evidence that SOCS2 binds to the IGF-I receptor (IGF-IR) supports the novel possibility that SOCS2 limits IGF-I action. The current study tested the hypothesis that SOCS2 normally limits basal or IGF-I-induced intestinal growth and limits IGF-IR signaling in intestinal epithelial cells. Intestinal growth was assessed in mice homozygous for SOCS2 gene deletion (SOCS2 null) and wild-type (WT) littermates at different ages and in response to infused IGF-I or vehicle or EGF and vehicle. The effects of SOCS2 on IGF-IR signaling were examined in ex vivo cultures of SOCS2 null and WT intestine and Caco-2 cells. Compared with WT, SOCS2 null mice showed significantly enhanced small intestine and colon growth, mucosal mass, and crypt cell proliferation and decreases in radiation-induced crypt apoptosis in jejunum. SOCS2 null mice showed significantly greater growth responses to IGF-I in small intestine and colon. IGF-I-stimulated activation of IGF-IR and downstream signaling intermediates were enhanced in the intestine of SOCS2 null mice and were decreased by SOCS2 overexpression in Caco-2 cells. SOCS2 bound directly to the endogenous IGF-IR in Caco-2 cells. The intestine of SOCS2 null mice also showed enhanced growth responses to infused EGF. We conclude that SOCS2 normally limits basal and IGF-I- and EGF-induced intestinal growth in vivo and has novel inhibitory effects on the IGF-IR tyrosine kinase pathway in intestinal epithelial cells.
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ABSTRACT: Objective To observe the effect of acupuncture-moxibustion on the expression of insulin-like growth factor-1 (IGF-1) and suppressor of cytokine signaling-2 (SOCS2) in colonic mucosa of rat models of ulcerative colitis (UC), and explore the mechanism of acupuncture-moxibustion therapy in treating UC. Methods The rats were randomized into a normal control (NC) group, a model control (MC) group, an herb-partitioned moxibustion (HPM) group and an electroacupuncture (EA) group, 8 in each group. The rat models of UC were established by immunological methods combined with local stimulation. The rats in the HPM and EA groups were given herb-partitioned moxibustion and electroacupuncture treatments respectively, once every day, lasting for 14 d. The morphological variations of rat’s colonic mucosa were observed under light microscope; the colonic mucosal mucin was detected by PAS-AB and HID-AB staining methods; the expression of IGF-1 and SOCS2 was assayed by the immunohistochemical method. Results In the rat models of UC, ulceration and inflammation of the colon were revealed by light microscope. The concentration of colonic mucosal mucin was reduced (P<0.01), while the expression of IGF-1 had an increase (P<0.01), and the expression of SOCS2 was reduced (P<0.01). After HPM or EA treatment, the pathological injuries of colonic mucosa had improved, the concentration of mucin increased (P<0.01), the expression of IGF-1 decreased (P<0.01), and the expression of SOCS2 increased (P<0.01). Conclusion The secretion of mucosal mucin in rat UC decreased, the expression of IGF-1 was significantly higher, while the expression of SOCS2 was remarkably lower; both HPM and EA can help improve the damage of colonic mucosa in rat UC, and modulate the secretion of mucin, as well as regulate the expression of IGF-1 and SOCS2 in the colonic mucosa.
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ABSTRACT: At the "4th International Meeting on Inflammatory Bowel Diseases: on the Way to New Therapies," Capri, 2006, genetics, bacteria-host interactions, immunomodulation, and tissue response were discussed deeply in order to understand, rationalize, and develop novel therapies. About genetics, the importance of a better understanding of the nature of known loci and of the putative associations was stressed. It was confirmed that genotype-phenotype associations in inflammatory bowel disease (IBD) have important clinical and therapeutic implications. The importance of the search for dominant bacterial antigens in chronic immune-mediated intestinal inflammation emerged, as well as knowledge of cellular and molecular mechanisms of bacterial-host interactions. It was discussed how innate and adaptive immunity signaling events can perpetuate chronic inflammation. Signal transduction pathways provide an intracellular mechanism by which cells respond and adapt to environmental stress. The identification of these signals have led to a greater understanding of the pathogenesis of IBD and pointed to potential therapeutic targets. It was shown that immune homeostasis is lost in IBD, resulting in a complex tissue response involving the action of immune and nonimmune cells. The nonimmune tissue response in IBD could be regarded as a new target for control of chronic intestinal inflammation. The changing role of biotherapy in IBD was widely discussed and in particular the anti-TNF-alpha monoclonal antibodies. Granulocyte-colony stimulating factor (GM-CSF) and stem cells therapies were also discussed. The risk-to-benefit ratio of the novel therapies was analyzed in detail. Finally, future directions for basic science and the unmet needs for clinical practice were presented.
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