Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IκBα

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear and pituitary cells. It has also been shown to counteract cortisol-induced inhibition of inflammatory cytokine secretion. The purpose of this study was to determine whether MIF antagonized the effect of hydrocortisone on the NF-kappa B/I kappa B signal transduction pathway in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells. Physiological doses of hydrocortisone (50-200 ng/ml) diminished both the LPS-stimulated decrease in cytosolic I kappa B alpha levels and the subsequent increase in nuclear NF-kappa B DNA binding. In the presence of both LPS and hydrocortisone, 1 ng/ml of MIF antagonized the effects of hydrocortisone, resulting in decreased cytosolic I kappa B alpha levels (P< 0.05) and increased nuclear NF-kappa B DNA binding (P< 0.05). In the absence of hydrocortisone, MIF had no effect on LPS-induced decreases in I kappa B alpha. In the absence of LPS, MIF inhibited hydrocortisone-induced increases in I kappa B alpha (P = 0.03). Thus the mechanism by which MIF antagonizes the effect of hydrocortisone on the NF-kappa B/IkB signal transduction pathway is through inhibiting the ability of hydrocortisone to increase cytosolic I kappa B alpha.