Sex Steroid Regulation of Macrophage Migration Inhibitory Factor in Normal and Inflamed Colon in the Female Rat

Background & Aims: Sex steroids influence IBD symptoms. Macrophage migration inhibitory factor (MIF), a target of sex steroids in other inflammatory models, promotes interleukin (IL)-1β and tumor necrosis factor (TNF)-α release in colitis. We investigated whether estradiol and progesterone influence MIF, IL-1β, and TNF-α production in experimental colitis. Methods: Colonic MIF, IL-1β, and TNF-α levels were measured in cyclic and ovariectomized rats, with or without estradiol benzoate (EB) or progesterone (P) replacement. MIF distribution was assessed by immunohistochemistry. Cytokines, myeloperoxidase activity, macroscopic damage, and plasma corticosterone were assessed 24 hours after intrarectal trinitrobenzene sulfonic acid (TNBS), with and without neutralizing anti-MIF antibody. Effects of EB and P on myeloperoxidase activity and MIF concentration were also assessed at 7 days in dextran sulfate sodium-induced colitis. Results: Basal IL-1β and TNF-α contents did not fluctuate during the estrous cycle, while MIF concentrations increased from estrus (estrogen dominance) to metestrus (P dominance; P < .05). EB and P treatment mimicked these effects in ovariectomized rats, and similarly altered MIF immunostaining. Progesterone dominance aggravated TNBS colitis in comparison with estrogen. Progesterone enhanced TNBS-induced MIF (P < .001) and TNF-α (P < .01) production, while EB decreased MIF (P < .01) and IL-β levels (P < .01). Anti-MIF antibody prevented P-mediated up-regulation of TNF-α, improved TNBS colitis, and enhanced plasma corticosterone. At 7 days after dextran sulfate sodium, EB decreased myeloperoxidase activity and MIF concentration, while P had no effect. Conclusions: Estrogen decreases while progesterone increases MIF production in the female rat colon. Changes in basal MIF contents may affect colon susceptibility to inflammation, by modulating TNF-α and IL-1β production during early stages of colitis.

Abbreviations used in this paper: DNBS, dinitrobenzene sulfonic acid, DSS, dextran sulfate sodium, EB, estradiol benzoate, ELISA, enzyme-linked immunosorbent assay, IL, interleukin, MDS, macroscopic damage score, MIF, macrophage migration inhibitory factor, MPO, myeloperoxidase, OVX, ovariectomized, P, progesterone, TNBS, trinitrobenzene sulfonic acid, TNF, tumor necrosis factor