{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:02:49Z","timestamp":1791129769975,"version":"4.1.0"},"reference-count":55,"publisher":"The Endocrine Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,6,1]]},"abstract":"<jats:p>In patients with septic shock (n = 32), multitrauma (n = 8), and hospitalized matched controls (n = 41), we serially measured serum macrophage inhibitory factor (MIF), cortisol, plasma ACTH, tumor necrosis factor-\u03b1, and interleukin-6 (IL-6) immunoreactivity during 14 days or until discharge\/death. MIF levels were significantly elevated on day 1 in septic shock (14.3 \u00b1 4.5 \u03bcg\/L), as opposed to trauma (3.1 \u00b1 1.7 \u03bcg\/L) and control patients (2.5 \u00b1 2.1 \u03bcg\/L). The time course of MIF, parallel to cortisol, but in contrast to ACTH, showed persistently elevated levels in septic patients. On admission, nonsurvivors of septic shock (n = 11) showed significantly higher MIF levels than survivors (18.4 \u00b1 4.8 and 10.2 \u00b1 4.2 \u03bcg\/L, respectively). Patients with septic adult respiratory distress syndrome (ARDS; n = 8) showed higher MIF levels than those who did not develop ARDS (19.4 \u00b1 4.7 vs. 9.2 \u00b1 4.3 \u03bcg\/L, respectively). Multiple logistic regression analysis demonstrated that both MIF and ARDS were independent predictors of adverse outcome. On admission, tumor necrosis factor-\u03b1, IL-6, procalcitonin, and lipopolysaccharide-binding protein levels were higher in patients with septic shock than in patients with multitrauma. In septic patients, regression analysis showed significant correlations between MIF and cortisol as well as between MIF and IL-6 levels and disease severity scores. No relation was found between MIF and markers of the acute phase response (procalcitonin, C- reactive protein, and lipopolysaccharide-binding protein). In multitrauma patients, MIF levels were not elevated at any time point and were not related to other variables.<\/jats:p><jats:p>Our data suggest that during immune-mediated inflammation (such as septic shock) MIF is an important neuroendocrine mediator: a contraregulator of the immunosuppressive effects of glucocorticoids.<\/jats:p>","DOI":"10.1210\/jcem.86.6.7570","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:06:53Z","timestamp":1389200813000},"page":"2811-2816","source":"Crossref","is-referenced-by-count":91,"title":["Macrophage Migration Inhibitory Factor and Hypothalamo-Pituitary-Adrenal Function during Critical Illness"],"prefix":"10.1210","volume":"86","author":[{"given":"Albertus","family":"Beishuizen","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (A.B.), 7500 KA Enschede, The Netherlands"},{"name":"Medical Intensive Care Unit, Free University Hospital (A.B., L.G.T.), 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lambertus G.","family":"Thijs","sequence":"additional","affiliation":[{"name":"Medical Intensive Care Unit, Free University Hospital (A.B., L.G.T.), 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Haanen","sequence":"additional","affiliation":[{"name":"Clinical Chemistry (I.V., C.H.), Medical Spectrum Twente, Hospital Group, 7500 KA Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istva\u0301n","family":"Vermes","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (A.B.), 7500 KA Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071618500950000_R1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0065-2776(08)60598-2","article-title":"Role of macrophage migration inhibitory factor in the regulation of the immune response.","volume":"66","author":"Metz","year":"1997","journal-title":"Adv Immunol"},{"key":"2020071618500950000_R2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BFb0033647","article-title":"Macrophage migration inhibitory factor: cytokine, hormone, or enzyme?","volume":"139","author":"Swope","year":"1999","journal-title":"Rev Physiol Biochem Pharmacol"},{"key":"2020071618500950000_R3","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/BF01878495","article-title":"The emerging role of MIF in septic shock and infection.","volume":"8","author":"Bernhagen","year":"1994","journal-title":"Biotherapy"},{"key":"2020071618500950000_R4","doi-asserted-by":"crossref","first-page":"11383","DOI":"10.1073\/pnas.95.19.11383","article-title":"Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria.","volume":"95","author":"Calandra","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071618500950000_R5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1615\/CritRevImmunol.v17.i1.30","article-title":"Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system.","volume":"17","author":"Calandra","year":"1997","journal-title":"Crit Rev Immunol"},{"key":"2020071618500950000_R6","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/S1357-4310(97)01133-7","article-title":"Macrophage migration inhibitory factor: a regulator of glucocorticoid activity with a critical role in inflammatory disease.","volume":"3","author":"Donnelly","year":"1997","journal-title":"Mol Med Today"},{"key":"2020071618500950000_R7","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/377068a0","article-title":"MIF as a glucocorticoid-induced modulator of cytokine production.","volume":"377","author":"Calandra","year":"1995","journal-title":"Nature"},{"key":"2020071618500950000_R8","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s000110050503","article-title":"Glucocorticoid regulation of inflammation: the plot thickens.","volume":"48","author":"Morand","year":"1999","journal-title":"Inflamm Res"},{"key":"2020071618500950000_R9","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/365756a0","article-title":"MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia.","volume":"365","author":"Bernhagen","year":"1993","journal-title":"Nature"},{"key":"2020071618500950000_R10","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1084\/jem.179.6.1895","article-title":"The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor.","volume":"179","author":"Calandra","year":"1994","journal-title":"J Exp Med"},{"key":"2020071618500950000_R11","first-page":"39","article-title":"Macrophage migration inhibitory factor: a counter-regulator of glucocorticoid action and critical mediator of septic shock.","volume":"47","author":"Calandra","year":"1995","journal-title":"J Inflamm"},{"key":"2020071618500950000_R12","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/BF03401892","article-title":"Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland.","volume":"1","author":"Nishino","year":"1995","journal-title":"Mol Med"},{"key":"2020071618500950000_R13","first-page":"235","article-title":"Migration inhibitory factor expression in experimentally induced endotoxemia.","volume":"150","author":"Bacher","year":"1997","journal-title":"Am J Pathol"},{"key":"2020071618500950000_R14","first-page":"1238","article-title":"Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone.","volume":"80","author":"Vermes","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071618500950000_R15","first-page":"1827","article-title":"Acute and prolonged critical illness as different neuroendocrine paradigms.","volume":"83","author":"Van den Berghe","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071618500950000_R16","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1096\/fasebj.10.14.9002552","article-title":"MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid- induced regulator of the immune response.","volume":"10","year":"1996","journal-title":"FASEB J"},{"key":"2020071618500950000_R17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s001090050204","article-title":"Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features.","volume":"76","author":"Bernhagen","year":"1998","journal-title":"J Mol Med"},{"key":"2020071618500950000_R18","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1084\/jem.183.1.277","article-title":"An essential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction.","volume":"183","author":"Bernhagen","year":"1996","journal-title":"J Exp Med"},{"key":"2020071618500950000_R19","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1084\/jem.185.8.1455","article-title":"The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat.","volume":"185","author":"Lan","year":"1997","journal-title":"J Exp Med"},{"key":"2020071618500950000_R20","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1046\/j.1365-2567.1997.00311.x","article-title":"Macrophage migration inhibitory factor induces phagocytosis of foreign particles by macrophages in autocrine and paracrine fashion.","volume":"92","author":"Onodera","year":"1997","journal-title":"Immunology"},{"key":"2020071618500950000_R21","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.4049\/jimmunol.160.3.1285","article-title":"Protective effect on Leishmania major infection of migration inhibitory factor, TNF-\u03b1, and IFN-\u03b3 administered orally via attenuated Salmonella typhimurium.","volume":"160","author":"Xu","year":"1998","journal-title":"J Immunol"},{"key":"2020071618500950000_R22","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1046\/j.1365-2133.1999.03206.x","article-title":"Evidence for a role of macrophage migration inhibitory factor in psoriatic skin disease.","volume":"141","author":"Steinhoff","year":"1999","journal-title":"Br J Dermatol"},{"key":"2020071618500950000_R23","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1002\/1529-0131(199908)42:8<1601::AID-ANR6>3.0.CO;2-B","article-title":"Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids.","volume":"42","author":"Leech","year":"1999","journal-title":"Arthritis Rheum"},{"key":"2020071618500950000_R24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/BF03402061","article-title":"An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma.","volume":"5","author":"Chesney","year":"1999","journal-title":"Mol Med"},{"key":"2020071618500950000_R25","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1128\/IAI.68.4.2259-2267.2000","article-title":"Macrophage migration inhibitory factor release by macrophages after ingestion of Plasmodium chabaudi-infected erythrocytes: possible role in the pathogenesis of malarial anemia.","volume":"68","author":"Martiney","year":"2000","journal-title":"Infect Immun"},{"key":"2020071618500950000_R26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1084\/jem.189.2.341","article-title":"Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis.","volume":"189","author":"Bozza","year":"1999","journal-title":"J Exp Med"},{"key":"2020071618500950000_R27","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/72262","article-title":"Protection from septic shock by neutralization of macrophage migration inhibitory factor.","volume":"6","author":"Calandra","year":"2000","journal-title":"Nat Med"},{"key":"2020071618500950000_R28","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1378\/chest.101.6.1481","article-title":"The ACCP-SCCM consensus conference on sepsis and organ failure.","volume":"101","author":"Bone","year":"1992","journal-title":"Chest"},{"key":"2020071618500950000_R29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/00005373-197403000-00001","article-title":"The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care.","volume":"14","author":"Baker","year":"1974","journal-title":"J Trauma"},{"key":"2020071618500950000_R30","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/00003246-198510000-00009","article-title":"APACHE II: a severity of disease classification system.","volume":"13","author":"Knaus","year":"1985","journal-title":"Crit Care Med"},{"key":"2020071618500950000_R31","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction\/failure.","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensive Care Med"},{"key":"2020071618500950000_R32","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1164\/ajrccm.149.3.7509706","article-title":"The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.","volume":"149","author":"Bernard","year":"1994","journal-title":"Am J Respir Crit Care Med"},{"key":"2020071618500950000_R33","first-page":"74","article-title":"Time-resolved fluorometric immunoassay of macrophage migration inhibitory factor.","volume":"20","author":"Malmegrin","year":"2000","journal-title":"J Clin Ligand Assay"},{"key":"2020071618500950000_R34","author":"Beishuizen","year":"2000"},{"key":"2020071618500950000_R35","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1210\/jcem-73-1-111","article-title":"Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery.","volume":"73","author":"Naito","year":"1991","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071618500950000_R36","doi-asserted-by":"crossref","first-page":"9317","DOI":"10.1073\/pnas.97.16.9317","article-title":"Interleukin-6 is an essential, corticotropin-releasing hormone- independent stimulator of the adrenal axis during immune system activation.","volume":"97","author":"Bethin","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071618500950000_R37","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1056\/NEJM199505183322008","article-title":"The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.","volume":"332","year":"1995","journal-title":"N Engl J Med"},{"key":"2020071618500950000_R38","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1210\/edrv-17-1-64","article-title":"Immune-neuro-endocrine interactions: facts and hypotheses.","volume":"17","author":"Besedovsky","year":"1996","journal-title":"Endocr Rev"},{"key":"2020071618500950000_R39","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1097\/00003246-199806000-00001","article-title":"Procalcitonin-marker, or mediator?","volume":"26","year":"1998","journal-title":"Crit Care Med"},{"key":"2020071618500950000_R40","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/00024382-199910000-00004","article-title":"Procalcitonin and proinflammatory cytokine in interactions in sepsis.","volume":"12","author":"Whang","year":"1999","journal-title":"Shock"},{"key":"2020071618500950000_R41","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1111\/j.1749-6632.1998.tb09617.x","article-title":"Neurohormonal host defense in endotoxin shock.","volume":"840","year":"1998","journal-title":"Ann NY Acad Sci"},{"key":"2020071618500950000_R42","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1172\/JCI2338","article-title":"LPS-binding protein protects mice from septic shock caused by LPS or Gram-negative bacteria.","volume":"101","author":"Lamping","year":"1998","journal-title":"J Clin Invest"},{"key":"2020071618500950000_R43","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1086\/315093","article-title":"Relationship between plasma levels of lipopolysaccharide (LPS) and LPS- binding protein in patients with severe sepsis and septic shock.","volume":"180","author":"Opal","year":"1999","journal-title":"J Infect Dis"},{"key":"2020071618500950000_R44","doi-asserted-by":"crossref","first-page":"7849","DOI":"10.1073\/pnas.93.15.7849","article-title":"An essential regulatory role for macrophage migration inhibitory factor in T-cell activation.","volume":"93","author":"Bacher","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071618500950000_R45","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/35041591","article-title":"Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1.","volume":"408","author":"Kleemann","year":"2000","journal-title":"Nature"},{"key":"2020071618500950000_R46","first-page":"292","article-title":"The roles of prolactin, growth hormone, insulin-like growth factor-1, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency.","volume":"21","author":"Dorshkind","year":"2000","journal-title":"Endocr Rev"},{"key":"2020071618500950000_R47","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/383726a0","article-title":"Functional interactions between Stat5 and the glucocorticoid receptor.","volume":"383","author":"Stocklin","year":"1996","journal-title":"Nature"},{"key":"2020071618500950000_R48","doi-asserted-by":"crossref","first-page":"R1043","DOI":"10.1152\/ajpregu.2000.279.3.R1043","article-title":"Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic I\u03baB\u03b1","volume":"279","author":"Daun","year":"2000","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"key":"2020071618500950000_R49","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nm0397-320","article-title":"Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome.","volume":"3","author":"Donnelly","year":"1997","journal-title":"Nat Med"},{"key":"2020071618500950000_R50","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1164\/ajrccm.158.2.9707086","article-title":"Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation.","volume":"158","author":"Makita","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2020071618500950000_R51","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/72230","article-title":"MIF mediation of sepsis.","volume":"6","year":"2000","journal-title":"Nat Med"},{"key":"2020071618500950000_R52","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1097\/00003246-199804000-00002","article-title":"Corticosteroids in septic shock: resurrection of the last rites?","volume":"26","author":"Matot","year":"1998","journal-title":"Crit Care Med"},{"key":"2020071618500950000_R53","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1097\/00003246-199804000-00003","article-title":"Glucocorticoid treatment of sepsis and acute respiratory distress syndrome: time for a critical reappraisal.","volume":"26","author":"Meduri","year":"1998","journal-title":"Crit Care Med"},{"key":"2020071618500950000_R54","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1016\/S0140-6736(99)01346-X","article-title":"Relative eosinophilia and functional adrenal insufficiency in critically ill patients.","volume":"353","author":"Beishuizen","year":"1999","journal-title":"Lancet"},{"key":"2020071618500950000_R55","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.1210\/jcem.84.9.6011-2","article-title":"Relative eosinophilia (Thorn test) as a bioassay to judge the clinical relevance of cortisol values during severe stress.","volume":"84","author":"Beishuizen","year":"1999","journal-title":"J Clin Endocrinol Metab"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/86\/6\/2811\/9169419\/jcem2811.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/86\/6\/2811\/9169419\/jcem2811.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T14:59:36Z","timestamp":1688914776000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/86\/6\/2811\/2849254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,6,1]]},"references-count":55,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2001,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jcem.86.6.7570","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,6,1]]}}}