MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia

Abstract

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.

Promoter region polymorphism of macrophage migration inhibitory factor is strong risk factor for young onset of extensive alopecia areata

“…3,10 Since the molecular cloning of MIF, 11 this cytokine has been reevaluated as a proinflammatory cytokine and pituitaryderived hormone that potentiates endotoxemia. 12,13 It has been shown that T cells and macrophages secrete MIF in response to various proinflammatory stimuli such as endotoxins. 4 It is evident that the mechanisms of hair follicle dysfunction in AA are immunological and controlled by activated T cells.…”

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…ELISA analysis of MIF in the supernatants of cultured wtMEFs showed that maximal constitutive MIF secretion was measurable 4-8 h after medium change (3.3-6.3 ng/ml produced by a 200 000 cell culture), with secretion plateauing thereafter. As rMIF is somewhat less potent than endogenously produced MIF (Bernhagen et al, 1993), this concentration roughly corresponds to the optimum of the rMIF dose-response curve (50 ng/ml). In fact, a 20 min incubation with media from 4 h cultures of wtMEFs triggered Akt activation similar to 50 ng/ml activate Akt signaling in an autocrine manner, whereas MIF is also able to rapidly 'de novo' activate this pathway.…”

“…In fact, MIF is prestored intracellularly and released upon stimulation, but also continuously by cycling tumor cells (Bernhagen et al, 1993;Mitchell and Bucala, 2000;Flieger et al, 2003). Activation of sustained ERK signaling is mediated by autocrine MIF action (Mitchell et al, 1999).…”

“…Role for JAB1 in MIF secretion and autocrine MIFmediated Akt signaling Intracellular MIF is a store for MIF secretion via the unconventional export pathway (Bernhagen et al, 1993;Flieger et al, 2003) and interacts with JAB1 (Kleemann et al, 2000). We investigated the possibility that JAB1 could act as a regulator of MIF secretion to control Akt signaling by interference with the autocrine MIF loop.…”

“…MIF is secreted by immune and parenchymal cells upon inflammatory and stress stimulation, but is also expressed intracellularly in various cells, where it likely serves regulatory functions, that are mediated by protein-protein interactions (Calandra and Roger, 2003). MIF plays a pivotal role in the pathogenesis of acute and chronic inflammatory diseases including septic shock, rheumatoid arthritis and atherosclerosis (Bernhagen et al, 1993;Calandra and Roger, 2003;Morand et al, 2006).…”