2nd Annual BMRP Investigator Meeting - Abstract

Growth Hormone Reduces Colon STAT3 Activation and Improves Disease Activity in Experimental Colitis

Lee A. Denson^a, Xiaonan Han, Lisa M. DiFedele and Danuta Sosnowska

Departments of Pediatrics and Yale Child Health Research Center, Yale University School of Medicine (New Haven, Connecticut, U.S.A.)

Background:  Interleukin-6 (IL-6) activation of the STAT3 transcription factor contributes to chronic inflammation in murine colitis and human inflammatory bowel disease (IBD).  Suppressors of cytokine signaling 3 (SOCS-3) is a negative regulator of this pathway.  Growth hormone (GH) has been shown to reduce disease activity and promote mucosal healing in colitis.   Anabolic effects of GH are mediated via activation of STAT5; GH target genes include insulin-like growth factor 1 (IGF-1) and SOCS-3.  However, the molecular basis for a beneficial effect of GH in colitis was not known.  We hypothesized that GH would ameliorate disease activity in colitis, and that this would involve modulation of STAT3/5 activation.

Methods:  Interleukin-10 null (IL-10) mice with colitis and wild type (WT) controls received single (1 mcg/gm IP 30 minutes prior to sacrifice) or chronic (3 mcg/gm SQ BID for two weeks) dose GH administration or PBS.  Weight, chow intake, and colon histopathology and STAT3/5, SOCS-3, and IGF-1 activation and/or expression were determined.  T84 human colon carcinoma cells were treated with IL-6 ± GH and STAT3/5 activation was determined.

Results:  Single dose GH administration activated STAT5 and upregulated IGF-1 in colon of WT mice; STAT5 and IGF-1 were constitutively induced in colitic mice, without additional up- regulation by GH.  STAT3 and SOCS-3 were also constitutively upregulated in colitis, in both colon epithelial cells (CEC) and lamina propria mononuclear cells (LPMC); GH administration significantly reduced STAT3 activation and SOCS-3 abundance in both cell populations.  GH treatment also reduced IL-6 dependent STAT3 activation in T84 cells.  Chronic GH administration improved weight gain and colon histopathology in colitic mice.  The improvement in colon histopathology was significantly associated with reduction in STAT3 activation.

Conclusions:  GH administration improved weight gain and reduced disease activity in IL-10 null mice with colitis.  The improvement in disease activity was related to a reduction in colonic STAT3 activation, but not to upregulation of local IGF-1 or SOCS-3 expression.  GH may be a useful adjunct therapy in IBD, both in terms of improving growth and body composition and in enhancing mucosal healing.

^aPrincipal Investigator