MIF IS A PITUITARY-DERIVED CYTOKINE THAT POTENTIATES LETHAL ENDOTOXEMIA

CYTOKINES are critical in the often fatal cascade of events that cause septic shock1-3. 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 stimuli4, and initiates the increase in systemic glucocorti coids that accompanies host stress responses6-8. To assess further the contribution of the pituitary to systemic inflammatory processes, we examined the secretory profile of cultured pituitary cells and whole p ituitaries in vivo after stimulation with bacterial lipopolysaccharide (LPS). Here we identify macrophage migration inhibitory factor (MIF)9 -11 as a major secreted protein released by anterior pituitary cells i n response to LPS stimulation. Serum analysis of control, hypophysecto mized 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 aga inst lethal endotoxaemia. We conclude that MIF plays a central role in the toxic response to endotoxaemia and possibly spetic shock.