Nonselective estrogens that can bind both classes of estrogen receptors (ERα and ERβ) also have anti-inflammatory activity, which appears to be the result of interference with the nuclear factor κB (NF-κB) pathway. Chadwick et al. exploited this activity to identify an estrogen receptor ligand, WAY-169916, that did not activate the estrogen receptor but antagonized NF-κB activity. In cells expressing exogenous ERα, WAY-169916 inhibited NF-κB reporter gene expression and interleukin 6 (IL-6) production upon exposure of cells to IL-1β. However, WAY-169916 did not increase expression of the enzyme creatine kinase (CK), which has an estrogen response element in its gene promoter. WAY-169916 inhibited NF-κB activity in cells expressing either the ERα or ERβ, and the activity was blocked by ER antagonists, indicating that inhibition of NF-κB activity required ER. The ability of WAY-169916 to selectively antagonize inflammatory responses was validated in mice fed on a high-fat diet and a rat model of inflammatory bowel disease (IBD). In the ovariectomized mice fed the high-fat diet, WAY-169916 did not increase uterine weight, which the nonselective estrogen did, but both the estrogen and WAY-169916 inhibited diet-induced increases in the mRNA for three inflammation-associated genes [vascular cell adhesion molecular 1 (VCAM1), tumor necrosis factor-α (TNF-α), and RANTES]. In the rats, WAY-169916 treatment eliminated the diarrhea associated with the IBD phenotype, and this effect was blocked by simultaneous treatment with an ER antagonist. Thus, ER ligands that are selective for the inhibitory effects of the ER on the NF-κB pathway may provide a promising therapeutic avenue for treatment of chronic inflammatory disease without causing unwanted side effects.
C. C. Chadwick, S. Chippari, E. Matelan, L. Borges-Marcucci, A. M. Eckert, J. C. Keith Jr., L. M. Albert, Y. Leathurby, H. A. Harris, R. A. Bhat, M. Ashwell, E. Trybulski, R. C. Winneker, S. J. Adelman, R. J. Steffan, D. C. Harnish, Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity. Proc. Natl. Acad. Sci. U.S.A. 102, 2543-2548 (2005). [Abstract] [Full Text]