MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia.
Cytokines are critical in the often fatal cascade of events that cause septic shock. One regulatory system that is likely to be important in controlling inflammatory responses is the neuroendocrine axis. The pituitary, for example, is ideally situated to integrate central and peripheral stimuli, and initiates the increase in systemic glucocorticoids that accompanies host stress responses. To assess further the contribution of the pituitary to systemic inflammatory processes, we examined the secretory profile of cultured pituitary cells and whole pituitaries in vivo after stimulation with bacterial lipopolysaccharide (LPS). Here we identify macrophage migration inhibitory factor (MIF) as a major secreted protein release by anterior pituitary cells in response to LPS stimulation. Serum analysis of control, hypophysectomized and T-cell-deficient (nude) mice suggests that pituitary-derived MIF contributes to circulating MIF present in the post-acute phase of endotoxaemia. Recombinant murine MIF greatly enhances lethality when co-injected with LPS and anti-MIF antibody confers full protection against lethal endotoxaemia. We conclude that MIF plays a central role in the toxic response to endotoxaemia and possibly septic shock.
Bernhagen
J
J
Picower Institute for Medical Research, Manhasset, New York 11030.
Calandra
T
T
Mitchell
R A
RA
Martin
S B
SB
Tracey
K J
KJ
Voelter
W
W
Manogue
K R
KR
Cerami
A
A
Bucala
R
R
D000210:Acute-Phase Reaction / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers; D004731:Endotoxins; D006801:Humans; D007016:Hypophysectomy; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D012772:Shock, Septic / Q000378:metabolism; D014115:Toxemia / Q000209:etiology / Q000378:metabolism*
D000906:Antibodies; D017931:DNA Primers; D004731:Endotoxins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; C044101:endotoxin, Escherichia coli