Sex steroid regulation of macrophage migration inhibitory factor in normal and inflamed colon in the female rat.
OBJECTIVE
Sex steroids influence IBD symptoms. Macrophage migration inhibitory factor (MIF), a target of sex steroids in other inflammatory models, promotes interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha release in colitis. We investigated whether estradiol and progesterone influence MIF, IL-1beta, and TNF-alpha production in experimental colitis.


METHODS
Colonic MIF, IL-1beta, and TNF-alpha 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-1beta and TNF-alpha 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-alpha (P < .01) production, while EB decreased MIF (P < .01) and IL-beta levels (P < .01). Anti-MIF antibody prevented P-mediated up-regulation of TNF-alpha, 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-alpha and IL-1beta production during early stages of colitis.
Houdeau
Eric
E
Neuro-Gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, Toulouse, France. eric.houdeau@toulouse.inra.fr
Moriez
Raphael
R
Leveque
Mathilde
M
Salvador-Cartier
Christel
C
Waget
Aurelie
A
Leng
Lin
L
Bueno
Lionel
L
Bucala
Richard
R
Fioramonti
Jean
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D030762:Estrous Cycle / Q000378:metabolism; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D010052:Ovariectomy; D009195:Peroxidase / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D012737:Sex Factors; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D012739:Gonadal Steroid Hormones; D053583:Interleukin-1beta; D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha; C074283:estradiol 3-benzoate; D011374:Progesterone; D004958:Estradiol; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase; D019746:Intramolecular Oxidoreductases; C515599:Mif protein, rat; D003345:Corticosterone