Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

Cho, Yoon Sang; Crichlow, G.V.; Vermeire, Jon J.; Leng, Lin; Du, Xin; Hodsdon, Michael E.; Bucala, Richard; Cappello, Michael; Gross, Matt; Gaeta, F. C. A.; Johnson, Kirk W.; Lolis, Elias

doi:10.1073/pnas.1002716107

Cited by 176 publications

(167 citation statements)

References 45 publications

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“…The retention of these reduced activities is attributed to some (but not all) inherent conformational flexibility in WT MIF that remains at the enzymatic and receptor sites despite formation of an intersubunit disulfide. In this respect, extraordinary NMR HSQC chemical shifts in response to binding and mutations have been previously observed for WT MIF (18,33,34), suggesting an increased propensity for conformational flexibility of MIF compared with other soluble proteins. The absence of full flexibility in the LT explains the inability to activate the receptor.…”

Section: Discussionmentioning

confidence: 95%

MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

Fan

Rajasekaran²,

Syed

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. In addition to its known receptor-mediated biological activities, MIF possesses a catalytic site of unknown function between subunits of a homotrimer. Each subunit contributes three β-strands to adjacent subunits to form a core seven-stranded β-sheet for each monomer. MIF monomers, dimers, or trimers have been reported, but the active form that binds and activates the MIF receptor (CD74) is still a matter of debate. A cysteine mutant (N110C) that covalently locks MIF into a trimer by forming a disulfide with Cys-80 of an adjacent subunit is used to study this issue. Partial catalytic activity and receptor binding to CD74 are retained by N110C (locked trimer), but there is no cellular signaling. Wild-type MIF-induced cellular signaling, in vivo lung neutrophil accumulation, and alveolar permeability are inhibited with a fivefold excess of N110C. NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer. The X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form. The structure also confirms these changes are consistent for the partial catalytic and receptor binding activities. The absence of any potential monomer and the retention of partial catalytic and receptor binding activities despite changes in conformation (and dynamics) in the mutant support an endogenous MIF trimer that binds and activates CD74 at nanomolar concentrations. This conclusion has implications for therapeutic development.mechanism | thermostable variant | ERK-1/2 activation M acrophage migration inhibitory factor (MIF) is a proinflammatory protein and an important regulator of innate and adaptive immunity (1). It localizes to the cytosol of all human nucleated cells and is released upon cellular stress to activate the receptor CD74 in complex with its signaling component CD44, or the chemokine receptors CXCR2 and CXCR4 to induce extracellular signal-regulated kinase 1/2 (ERK-1/2) activation (1-3). MIF promotes the cellular secretion of CXCL8, prostaglandin E2 (PGE 2 ), and other proinflammatory mediators, and it inhibits the anti-inflammatory activities of glucocorticoids (4). In addition to inflammation, MIF plays important roles in other diseases and is a drug target in phase I clinical trials for solid tumors (5, 6). MIF is a trimer with extensive subunit-subunit interactions, including a seven-stranded β-sheet for each monomer with β-strands contributed by adjacent subunits (7-9). An enzymatic site with an unknown substrate and a presumed tautomerase/isomerase activity exists between subunits similar to other proteins in the MIF superfamily (10). A key feature of these proteins is an invariant N-terminal residue, Pro-1, that functions as a catalytic base (11).Oligomerization plays an important role in the activity and regulation of a wide variety of proteins (12). Altho...

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Section: Discussionmentioning

confidence: 95%

MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

Fan

Rajasekaran²,

Syed

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…An analog of the anti-inflammatory drug ibudilast binds to a region proximal to the catalytic site, whereas the anti-oxidant ebselen disaggregates MIF trimers (39,40). Encouraged by these findings, we sought to obtain additional allosteric MIF inhibitors that neither compete for nor covalently modify the active site.…”

Section: Macrophage Migration Inhibitory Factor (Mif)mentioning

confidence: 99%

A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)

Bai

Asojo

Cirillo³

et al. 2012

Journal of Biological Chemistry

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Background: MIF is a pro-inflammatory cytokine implicated in autoimmune diseases. Results: A small molecule that binds to MIF and inhibits its cytokine activities was identified. Conclusion:The inhibitor binds in a unique region on MIF and reveals a new way to block the cytokine activities of MIF. Significance: The inhibitor is a valuable tool to design MIF-directed therapeutics for inflammatory diseases.

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“…Dose selection was based on previous animal pharmacology results 43 showing MN166 to be safe and well tolerated, yielding plasma concentrationtime profiles commensurate with high-dose regimens in clinical development. MN166 administered by this regimen yields plasma and CNS concentrations that are linked to molecular target actions, including, most potently, macrophage migration inhibitory factor (MIF) inhibition 44 and, secondarily, phosphodiesterases -4 and -10 inhibition. 45 The relevance of MIF inhibition in disorders of neuroimmune function, such as neuropathic pain, has recently been well demonstrated.…”

Section: Ibudilast (Mn166) Administrationmentioning

confidence: 99%

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Rodgers

Deming

Bercum

et al. 2014

Journal of Neurotrauma

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Traumatic brain injury (TBI) increases the risk of neuropsychiatric disorders, particularly anxiety disorders. Yet, there are presently no therapeutic interventions to prevent the development of post-traumatic anxiety or effective treatments once it has developed. This is because, in large part, of a lack of understanding of the underlying pathophysiology. Recent research suggests that chronic neuroinflammatory responses to injury may play a role in the development of post-traumatic anxiety in rodent models. Acute peri-injury administration of immunosuppressive compounds, such as Ibudilast (MN166), have been shown to prevent reactive gliosis associated with immune responses to injury and also prevent lateral fluid percussion injury (LFPI)-induced anxiety-like behavior in rats. There is evidence in both human and rodent studies that post-traumatic anxiety, once developed, is a chronic, persistent, and drug-refractory condition. In the present study, we sought to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety. We examined the efficacy of an anti-inflammatory treatment in decreasing anxiety-like behavior and reactive gliosis when introduced at 1 month after injury. Delayed treatment substantially reduced established LFPI-induced freezing behavior and reactive gliosis in brain regions associated with anxiety and continued neuroprotective effects were evidenced 6 months post-treatment. These results support the conclusion that neuroinflammation may be involved in the development and maintenance of anxiety-like behaviors after TBI.

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Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

Cited by 176 publications

References 45 publications

MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

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