Growth hormone and IBD: Reduction of intestinal inflammation, promotion of growth

Therapeutic approaches in childhood IBD using growth hormone could promote growth and intestinal healing

Children with Inflammatory Bowel Diseases (IBD) frequently experience problems with poor and delayed growth and intestinal bleeding. This in part is due to impaired actions of growth hormone, a naturally occurring compound that normally acts to promote both growth and healing.

About 10%, or 100,000 of the estimated 1 million Americans who suffer from IBD (either Crohn’s Disease, or ulcerative colitis) are under 18, according to the Crohn’s and Colitis Foundation of America. CCFA said IBD has been has been detected in infants as young as 18 months and can be particularly hard to diagnosis in children.

Initial symptoms may be nonspecific weight loss or delayed growth. The average delay in diagnosis is three years from the onset of symptoms in children.

About 60%-90% of children with Crohn’s and 15% of children with ulcerative colitis experience growth failure, CCFA statistics indicate.

In addition to weight loss and/or delayed growth, other IBD symptoms, which range from mild to severe and life-threatening, include any or all of the following:

1. Persistent diarrhea
2. Abdominal cramps
3. Rectal bleeding
4. Intermittent fever
5. Arthritic-like inflammation of the joints
6. Inflammation of the skin or eyes, and
7. Skin nodules and ulcers

Researchers Xiaonan Han, Erin Bonkowski and Lee Denson of the Department of Pediatric Gastroenterology, Cincinnati Childrens Hospital, Ohio, reported the results of their study “Growth hormone reduces STAT3 activation and modulates cellular apoptosis and proliferation in murine colitis” at an IBD translational conference sponsored by the American Physiological Society.

Dr. Denson’s laboratory has been investigating ways to improve the actions of growth hormone in IBD. Recently, utilizing an animal model of IBD, they determined that growth hormone itself is able to directly reduce inflammation in the diseased intestine, as well as promoting growth.

In the long run, “this may lead to new therapeutic approaches which will take advantage of these properties in both improving growth and intestinal healing in IBD,” Dr. Denson noted.

Background and results

STAT3 (signal transducer and activator of transcription-3) regulates disease activity in experimental colitis and human IBD. Suppressor of cytokine signaling 3 (SOCS-3) and Src-homology tyrosine phosphatase 2 (SHP2) are negative regulators of Il-6 dependent STAT3 activation via the gp130 receptor. Growth hormone (GH) reduces disease activity in experimental colitis, however, the molecular mechanism was not known.

The researchers hypothesized that “GH would ameliorate colitis by upregulating SOCS-3 or SHP2 and reducing STAT3 activation.” Their experiment showed that GH administration indeed did improve weight gain and colon histopathology in IL-10 null mice with colitis. This wasn’t associated with increases in either serum or colon IGF-1.

GH increased apoptosis of lamina propria mononuclear cells (LPMC), while reducing apoptosis and increasing proliferation of crypt epithelial cells (CEC). GH reduced STAT3 activation in both CEC and LPMC; the improvement in histopathology was associated with reduced STAT3 activation. Growth hormone also enhanced SHP2:gp130 binding under these conditions, while SOCS-3 abundance was reduced.

Direct effects of GH were investigated in tissue culture. Growth hormone treatment decreased constituitive STAT3 activation in IL-10 null mouse colon organ culture. As was observed in vivo, GH increased SHP2:gp130 association and reduced IL-6 dependent STAT3 activation in T84 human colon carcinoma cells.

Conclusion

The Cincinnati investigators found that growth hormone administration improved weight gain and reduced disease activity in IL-10 null mice with colitis. This was related to a reduction in STAT3 activation associated with increased SHP2:gp130 binding and alteration in CEC and LPMC apoptosis and proliferation. The results indicate that use of growth hormone in IBD would lead to new therapeutic approaches taking advantage of improving growth and intestinal healing.