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

doi:10.1053/j.gastro.2006.12.028

Gastroenterology

Volume 132, Issue 3, March 2007, Pages 982-993

https://doi.org/10.1053/j.gastro.2006.12.028 Get rights and content

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.

Section snippets

Animals

Adult female Wistar rats (Charles River, Saint-Aubin-Lès-Elbeuf, France) were housed in groups of 4 with free access to food and water, under a 12 hour:12 hour light:dark cycle. All protocols were approved by the local institutional Animal Care and Use Committee, in compliance with the European laws on the protection of animals (86/609/EEC).

Determination of Estrous Cycle Stages and Ovariectomy

In a first experiment, estrous cycle stages were assessed through daily vaginal smears, as previously described.³⁰ Only rats displaying regular cycles were

MIF, IL-1β, and TNF-α Colonic Contents During the Estrous Cycle, and Effect of Ovariectomy

MIF concentrations increased significantly from the follicular to the luteal phase of the cycle (Figure 1A) (301 ± 39 and 781 ± 135 ng/mg of protein in estrus and metestrus, respectively; P < .05). In the same rats, no significant variation was observed throughout the cycle for IL-1β (range, 28 ± 3 to 38 ± 5 pg/mg of protein) and TNF-α (range, 3.6 ± 0.1 to 4.1 ± 0.3 pg/mg of protein) (Figure 1B and C).

In OVX rats, MIF concentrations were decreased (117 ± 28 vs. 628 ± 85 ng/mg of protein in the

Discussion

The current study shows that female sex hormones are involved in the control of MIF expression in the normal and inflamed colon. In IBD and animal models of colitis, MIF is a proinflammatory cytokine that stimulates the production of TNF-α and IL-1β,20, 21 both playing a central role in the initiation and perpetuation of mucosal inflammation.37, 38, 39 Our study in female rats provides evidence of a relationship between basal MIF levels, estrous cycle-dependent hormonal status, and the capacity

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: Supported by the Institut National de la Recherche Agronomique (INRA).

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Basic–alimentary tractSex Steroid Regulation of Macrophage Migration Inhibitory Factor in Normal and Inflamed Colon in the Female Rat

Section snippets

Animals

Determination of Estrous Cycle Stages and Ovariectomy

MIF, IL-1β, and TNF-α Colonic Contents During the Estrous Cycle, and Effect of Ovariectomy

Discussion

Obstet Gynecol

Am J Gastroenterol

Cytokine

Gastroenterology

Gastroenterology

Fertil Steril

Exp Neurol

Am J Pathol

Gastroenterology

Pharmacol Biochem Behav

Peptides

Peptides

Cytokine

Pain

Neuroscience

Eur J Cancer

Gastroenterology

Obstet Gynecol

Cytokine

Lancet

Lancet

Gastroenterology

Gastroenterology

Influence of sex and disease on illness-related concerns in inflammatory bowel disease

Can J Gastroenterol

Health-related quality of life in patients with inflammatory bowel disease five years after the initial diagnosis

Scand J Gastroenterol

The epidemiology of inflammatory bowel disease in Canada: a population-based study

Am J Gastroenterol

Premarin-induced ischemic colitis

J Clin Gastroenterol

Risk factors for inflammatory bowel disease in the general population

Aliment Pharmacol Ther

Estradiol treatment ameliorates acetic acid-induced gastric and colonic injuries in rats

Inflammation

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

Am J Physiol Gastrointest Liver Physiol

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