Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1

Abstract

Cytokines are multifunctional mediators that classically modulate immune activity by receptor-mediated pathways. Macrophage migration inhibitory factor (MIF) is a cytokine that has a critical role in several inflammatory conditions but that also has endocrine and enzymatic functions. The molecular targets of MIF action have so far remained unclear. Here we show that MIF specifically interacts with an intracellular protein, Jab1, which is a coactivator of AP-1 transcription that also promotes degradation of the cyclin-dependent kinase inhibitor p27Kip1 (ref. 10). MIF colocalizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. MIF inhibits Jab1- and stimulus-enhanced AP-1 activity, but does not interfere with the induction of the transcription factor NFkappaB. Jab1 activates c-Jun amino-terminal kinase (JNK) activity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by increasing p27Kip1 expression through stabilization of p27Kip1 protein. Consequently, Jab1-mediated rescue of fibroblasts from growth arrest is blocked by MIF. Amino acids 50-65 and Cys 60 of MIF are important for Jab1 binding and modulation. We conclude that MIF may act broadly to negatively regulate Jab1-controlled pathways and that the MIF-Jab1 interaction may provide a molecular basis for key activities of MIF.

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

“…Recently, the growth-inhibiting effects induced on fibroblasts by MIF has been reported. 22 Imbalance between proinflammatory cytokines and cytokine antagonists or inhibitors is one of the factors that may predispose patients to the initiation or perpetuation of autoimmune diseases including AA. It is known that the proinflammatory mediators IL-1 and TNF-a are potent MIF polymorphism in extensive alopecia areata T Shimizu et al inhibitors of hair follicle cell proliferation, with a concomitant inhibition of hair growth.…”

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

“…Nuclear factor B (NF-B) has been shown to influence synovial hypertrophy via the protection of cells from tumor necrosis factor-mediated apoptosis (37). Direct evidence of NF-B activation by MIF is consistently lacking, however (38). NF-B and p53 are thought to have mutually antagonistic effects on tissue growth via competition for coactivator molecules, including CREB binding protein (39).…”

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

“…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 promotes cell proliferation and blockade of MIF by antibodies or genetic deletion leads to reduced cellular proliferation and inhibition of tumor growth and angiogenesis (Takahashi et al, 1998;Chesney et al, 1999;Hudson et al, 1999;Shimizu et al, 1999;Mitchell and Bucala, 2000;Bando et al, 2002;Amin et al, 2003;Nishihira et al, 2003). These effects may involve MIF-mediated regulation of CD74-dependent ERK mitogen-activated protein kinase (MAPK) signaling and activation of cytosolic phospholipase A2 (cPLA2) (Mitchell et al, 1999;Leng et al, 2003;Lue et al, 2006), modulation of activities of the tumor-associated protein c-Jun activation domain-binding protein-1 (JAB1) and signaling through the COP9 signalosome (CSN) (Kleemann et al, 2000;Burger-Kentischer et al, 2005). JAB1 is CSN5 of the CSN and functions as coactivator of activator protein-1 (AP-1)-driven gene expression and participates in CSN-mediated activation of SCF-E3 ligase-dependent proteasomal degradation of cell cycle regulators such as p27 or p53 (Chamovitz and Segal, 2001; Bech-Otschir et al, 2002; Wolf et al, 2003).…”