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1 CVMDR, Wyeth Research, Collegeville, PA, USA
2 CVMDR, Wyeth Research, Cambridge, MA, USA
3 Inflammation, Wyeth Research, Cambridge, MA, USA
* To whom correspondence should be addressed. E-mail: Harnisd{at}wyeth.com.
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
and ER
) 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-ethynyl-17-estradiol (EE) for 5 days. EE treatment dramatically improved stool scores after only 3 days. Histological scores in the degree of ulceration, inflammatory cell infiltration, fibrosis and lesion depth of the colon were also improved by EE treatment.
Since neutrophil infiltration into the colon is involved in the development and propagation of disease, myeloperoxidase activity (MPO) was measured. MPO levels were reduced by
80% by EE treatment. Cotreatment with the pure ER antagonist ICI 182,780 (ICI) blocked the effects of EE on stool character, MPO activity and the 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 the colons from estrogen treated rats. In addition, a direct effect of estrogen on bone marrow derived mast cells (BMMC) 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.
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