title: Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IkappaBalpha.
abstract: 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-kappaB/IkappaB 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 IkappaBalpha levels and the subsequent increase in nuclear NF-kappaB DNA binding. In the presence of both LPS and hydrocortisone, 1 ng/ml of MIF antagonized the effects of hydrocortisone, resulting in decreased cytosolic IkappaBalpha levels (P < 0.05) and increased nuclear NF-kappaB DNA binding (P < 0.05). In the absence of hydrocortisone, MIF had no effect on LPS-induced decreases in IkappaBalpha. In the absence of LPS, MIF inhibited hydrocortisone-induced increases in IkappaBalpha (P = 0.03). Thus the mechanism by which MIF antagonizes the effect of hydrocortisone on the NF-kB/IkappaB signal transduction pathway is through inhibiting the ability of hydrocortisone to increase cytosolic IkappaBalpha.
authors.affiliation: Intercollege Physiology Program, Noll Physiological Research Center, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Daun
authors.forename: J G
authors.initials: JG
authors.lastname: Cannon
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014316:Tritium
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014316:Tritium; D000072000:NF-KappaB Inhibitor alpha; D006854:Hydrocortisone