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Am J Physiol Gastrointest Liver Physiol 286: G118-G125, 2004. First published September 4, 2003; doi:10.1152/ajpgi.00024.2003
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HORMONES AND SIGNALING

Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease

Douglas C. Harnish,1 Leo M. Albert,2 Yelena Leathurby,2 Amy M. Eckert,1 Agnes Ciarletta,3 Marion Kasaian,3 and James C. Keith, Jr.2

1Cardiovascular and Metabolic Disease Research, Wyeth, Collegeville, Pennsylvania 19426; and 2Cardiovascular and Metabolic Disease Research and 3Inflammation Research, Wyeth, Cambridge, Massachusetts 02140

Submitted 16 January 2003 ; accepted in final form 28 August 2003

A well-established model of bowel inflammation is the HLA-B27 transgenic rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens have previously been shown to modulate the immune system, and both estrogen receptors (ER{alpha} and ER{beta}) are present in the intestine and cells of the immune system. Therefore, the ability of estrogen to ameliorate disease progression in the HLA-B27 transgenic rat was determined. HLA-B27 transgenic rats with chronic diarrhea were treated with 17{alpha}-ethynyl-17{beta}-estradiol (EE) for 5 days. EE treatment dramatically improved stool scores after only 3 days. Histological scores of the degree of ulceration, inflammatory cell infiltration, fibrosis, and lesion depth of the colon were also improved by EE treatment. Because neutrophil infiltration into the colon is involved in the development and propagation of disease, myeloperoxidase (MPO) activity was measured. MPO levels were reduced by 80% by EE treatment. Cotreatment with the pure ER antagonist ICI-182780 (ICI) blocked the effects of EE on stool character, MPO activity, and histology scores, strongly suggesting that the activity of EE is mediated through ER. Mast cell proteases can promote neutrophil infiltration, and gene expression analysis demonstrated that mast cell protease 1, 3, and 4 mRNA were all decreased in colons from estrogen-treated rats. In addition, a direct effect of estrogen on bone marrow-derived mast cell activity was demonstrated, suggesting that ER-mediated inactivation of mast cells may contribute to the improvement in the clinical sign and histological scores in this model.

mast cells; estrogen receptor



Address for reprint requests and other correspondence: D. C. Harnish, 500 Arcola Rd., Collegeville, PA 19426 (E-mail: Harnisd{at}wyeth.com).




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