Macrophage migration inhibitory factor (MIF) is rendered enzymatically inactive by myeloperoxidase-derived oxidants but retains its immunomodulatory function

Dickerhof, Nina; Schindler, Lisa; Bernhagen, Jürgen; Hampton, Mark B.

doi:10.1016/j.freeradbiomed.2015.09.009

Cited by 20 publications

(35 citation statements)

References 92 publications

(136 reference statements)

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“…). This modification impaired the tautomerase activity, but not immunomodulatory activity, of MIF . However, in the present study, we assessed only monocytes, without adding these molecules.…”

Section: Discussionmentioning

confidence: 85%

Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex–Mediated Activation of the NLRP3 Inflammasome

Shin

Kang

Wahl

et al. 2018

Arthritis & Rheumatology

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The U1 snRNP immune complex is a specific stimulus of MIF production in human monocytes, with MIF having an upstream role in defining the inflammatory characteristics of activated monocytes by regulating NLRP3 inflammasome activation and downstream IL-1β production. These findings provide mechanistic insight and a therapeutic rationale for targeting MIF in subgroups of lupus patients, such as those classified as high genotypic MIF expressers or those with anti-snRNP antibodies.

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Section: Discussionmentioning

confidence: 85%

Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex–Mediated Activation of the NLRP3 Inflammasome

Shin

Kang

Wahl

et al. 2018

Arthritis & Rheumatology

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“…Another possibility could involve differing modes of action on MIF itself, where some molecules deactivate MIF pro-inflammatory activity in a manner independent of tautomerase inhibition. The utility of the tautomerase site in predicting MIF inflammatory activities has been a topic of some debate, with several groups showing inflammatory activity even in tautomerase-compromised MIF proteins or peptide fragments (69,70), and a recent study indicated that the extent of solvent exposure in MIF tautomerase inhibitors may be an important element in their interference with MIF-CD74 binding and subsequent inflammatory effects (71). Future study is clearly needed to clarify the source of these anti-inflammatory profiles, which could have important implications to MIF drug design.…”

Section: Discussionmentioning

confidence: 99%

“…Although the production of cytokines in response to MIF stimulation alone is controversial, the production of IL-8 by MIF stimulation of peripheral blood monocytes has been confirmed in multiple contexts (46,69). Human peripheral blood monocytes purified by adherence were plated at a density of ϳ2 ϫ 10 5 cells/ well in a 96-well plate.…”

Section: Methodsmentioning

confidence: 99%

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Bloom

Metz

Nalawade

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerMacrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in a broad range of inflammatory and oncologic diseases. MIF is unique among cytokines in terms of its release profile and inflammatory role, notably as an endogenous counter-regulator of the anti-inflammatory effects of glucocorticoids. In addition, it exhibits a catalytic tautomerase activity amenable to the design of high affinity small molecule inhibitors. Although several classes of these compounds have been identified, biologic characterization of these molecules remains a topic of active investigation. In this study, we used in vitro LPS-driven assays to characterize representative molecules from several classes of MIF inhibitors. We determined that MIF inhibitors exhibit distinct profiles of anti-inflammatory activity, especially with regard to TNF␣. We further investigated a molecule with relatively low anti-inflammatory activity, compound T-614 (also known as the anti-rheumatic drug iguratimod), and found that, in addition to exhibiting selective MIF inhibition in vitro and in vivo, iguratimod also has additive effects with glucocorticoids. Furthermore, we found that iguratimod synergizes with glucocorticoids in attenuating experimental autoimmune encephalitis, a model of multiple sclerosis. Our work identifies iguratimod as a valuable new candidate for drug repurposing to MIF-relevant diseases, including multiple sclerosis.

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“…49,50 Nevertheless, other researchers found that the immunological activity of MIF can be functionally dissociated from its tautomerase activity. 51 In contrast to the tautomerase activity which is dispensable for the biological activity, the TPOR activity, mediated through a conserved Cys-57-Ala-Leu-Cys-60 (CXXC) motif, 33 plays a critical role in cellular redox homeostasis. 33 Moreover, residue Cys-60 is also crucial for the interaction interface between MIF and JAB1/CSN5.…”

Section: Oba Suppresses Proinflammatory Mediator Release Through Inmentioning

confidence: 99%

Obacunone causes sustained expression of MKP‐1 thus inactivating p38 MAPK to suppress pro‐inflammatory mediators through intracellular MIF

Gao

Hou

Liu

et al. 2017

J of Cellular Biochemistry

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Obacunone (OBA) is a highly oxygenated triterpenoid with various pharmacological activities. In this study, we explored its anti-inflammatory effect and underlying mechanisms in LPS-activated macrophages. Our data showed that OBA potently decreased pro-inflammatory mediators (eg, NO, IL-6, IL-1β, and MCP-1) at the transcriptional and translational levels without cytotoxicity. A mechanism study showed that OBA significantly suppressed p38-mediated AP-1 signaling by stabilizing the mRNA of mitogen-activated protein kinase phosphatase 1 (MKP-1), thus prolonging the expression time of the MKP-1 protein. Next, we used computational target-fishing technology to predict the possible target of OBA. Only one potential target, macrophage migration inhibitory factor (MIF), was presented.Experimentally, the interaction between OBA and MIF was also confirmed. By using an anti-mouse MIF antibody, extracellular MIF (exMIF) was neutralized. Our results showed that autocrine MIF had slight influence on the pro-inflammatory mediator production. Correspondingly, the anti-inflammatory activity of OBA was also not affected. Accordingly, we knocked down the MIF gene in RAW 264.7 cells and obtained stable MIF deficient cells MIF(−), in which the effects of OBA on p38 phosphorylation, AP-1 activation, and pro-inflammatory mediator production in response to LPS nearly disappeared. In contrast to MIF(+) cells, the MKP-1 protein expression time of the MIF(−) cells was markedly prolonged. We conclude that OBA exerts its anti-inflammatory effect by targeting intracellular MIF (inMIF) inhibition to regulate the MKP-1/p38/AP-1 pathway. Our findings also provide a chain of evidence that the inhibition of inMIF, rather than exMIF, may become a novel target for inflammation.

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Macrophage migration inhibitory factor (MIF) is rendered enzymatically inactive by myeloperoxidase-derived oxidants but retains its immunomodulatory function

Cited by 20 publications

References 92 publications

Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex–Mediated Activation of the NLRP3 Inflammasome

Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex–Mediated Activation of the NLRP3 Inflammasome

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Obacunone causes sustained expression of MKP‐1 thus inactivating p38 MAPK to suppress pro‐inflammatory mediators through intracellular MIF

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