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Tiffany Sun,
Thomas Holowka,
Yan Song, Swen Zierow,
Lin Leng,
Yibang Chen,
Huabao Xiong,
Jason Griffith,
Mehdi Nouraie,
Philip E Thuma,
Elias Lolis,
Chris J Janse,
Victor R Gordeuk,
Kevin Augustijn,
Richard Bucala
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ABSTRACT: The inability to acquire protective immunity against Plasmodia is the chief obstacle to malaria control, and inadequate T-cell responses may facilitate persistent blood-stage infection. Malaria is characterized by a highly inflammatory cytokine milieu, and the lack of effective protection against infection suggests that memory T cells are not adequately formed or maintained. Using a genetically targeted strain of Plasmodium berghei, we observed that the Plasmodium ortholog of macrophage migration inhibitory factor enhanced inflammatory cytokine production and also induced antigen-experienced CD4 T cells to develop into short-lived effector cells rather than memory precursor cells. The short-lived effector CD4 T cells were more susceptible to Bcl-2-associated apoptosis, resulting in decreased CD4 T-cell recall responses against challenge infections. These findings indicate that Plasmodia actively interfere with the development of immunological memory and may account for the evolutionary conservation of parasite macrophage migration inhibitory factor orthologs.
Proceedings of the National Academy of Sciences 07/2012; 109(31):E2117-26. · 9.68 Impact Factor
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Melanie Merk, Swen Zierow,
Lin Leng,
Rituparna Das,
Xin Du,
Wibke Schulte,
Juan Fan,
Hongqi Lue,
Yibang Chen,
Huabao Xiong,
Frederic Chagnon,
Jürgen Bernhagen,
Elias Lolis,
Gil Mor,
Olivier Lesur,
Richard Bucala
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ABSTRACT: Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the immune response. Neutralization or genetic deletion of MIF does not completely abrogate activation responses, however, and deletion of the MIF receptor, CD74, produces a more pronounced phenotype than MIF deficiency. We hypothesized that these observations may be explained by a second MIF-like ligand, and we considered a probable candidate to be the protein encoded by the homologous, D-dopachrome tautomerase (D-DT) gene. We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. Circulating D-DT levels correlate with disease severity in sepsis or malignancy, and the specific immunoneutralization of D-DT protects mice from lethal endotoxemia by reducing the expression of downstream effector cytokines. These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology.
Proceedings of the National Academy of Sciences 08/2011; 108(34):E577-85. · 9.68 Impact Factor
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Heng Ma,
Jingying Wang,
D Paul Thomas,
Chao Tong,
Lin Leng,
Wenkui Wang,
Melanie Merk, Swen Zierow,
Jürgen Bernhagen,
Jun Ren,
Richard Bucala,
Ji Li
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ABSTRACT: Elderly patients are more sensitive than younger patients to myocardial ischemia, which results in higher mortality. We investigated how aging affects the cardioprotective AMP-activated protein kinase (AMPK) signaling pathway.
Ischemic AMPK activation was impaired in aged compared with young murine hearts. The expression and secretion of the AMPK upstream regulator, macrophage migration inhibitory factor (MIF), were lower in aged compared with young adult hearts. Additionally, the levels of hypoxia-inducible factor 1alpha, a known transcriptional activator of MIF, were reduced in aged compared with young hearts. Ischemia-induced AMPK activation in MIF knockout mice was blunted, leading to greater contractile dysfunction in MIF-deficient than in wild-type hearts. Furthermore, intramyocardial injection of adenovirus encoding MIF in aged mice increased MIF expression and ischemic AMPK activation and reduced infarct size.
An impaired MIF-AMPK activation response in senescence thus may be attributed to an aging-associated defect in hypoxia-inducible factor 1alpha, the transcription factor for MIF. In the clinical setting, impaired cardiac hypoxia-inducible factor 1alpha activation and consequent reduced MIF expression may play an important role in the increased susceptibility to myocardial ischemia observed in older cardiac patients.
Circulation 07/2010; 122(3):282-92. · 14.74 Impact Factor
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Melanie Merk,
John Baugh, Swen Zierow,
Lin Leng,
Utpal Pal,
Seung Joon Lee,
Antje D Ebert,
Yuka Mizue,
John O Trent,
Robert Mitchell,
Walter Nickel,
Paula B Kavathas,
Jürgen Bernhagen,
Richard Bucala
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ABSTRACT: Macrophage migration inhibitory factor (MIF) is a leaderless protein that is secreted from cells by a specialized, nonclassical export pathway. The release of MIF nevertheless is regulated and its production in response to different inflammatory, mitogenic, and hormonal stimuli plays an important role in diverse physiologic and pathologic processes. We report herein the identification of the Golgi complex-associated protein p115 as an intracellular binding partner for MIF. MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. The depletion of p115 from monocytes/macrophages decreases the release of MIF but not other cytokines following inflammatory stimulation or intracellular bacterial infection. Notably, the small molecule MIF inhibitor 4-iodo-6-phenylpyrimidine inhibits MIF secretion by targeting the interaction between MIF and p115. These data reveal p115 to be a critical intermediary component in the regulated secretion of MIF from monocytes/macrophages.
The Journal of Immunology 07/2009; 182(11):6896-906. · 5.79 Impact Factor
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Millicent Winner,
Jason Meier, Swen Zierow,
Beatriz E Rendon,
Gregg V Crichlow,
Randall Riggs,
Richard Bucala,
Lin Leng,
Ned Smith,
Elias Lolis,
John O Trent,
Robert A Mitchell
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ABSTRACT: Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.
Cancer Research 10/2008; 68(18):7253-7. · 7.86 Impact Factor
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Daniela Kamir, Swen Zierow,
Lin Leng,
Yoonsang Cho,
Yira Diaz,
Jason Griffith,
Courtney McDonald,
Melanie Merk,
Robert A Mitchell,
John Trent,
Yibang Chen,
Yuen-Kwan Amy Kwong,
Huabao Xiong,
Jon Vermeire,
Michael Cappello,
Diane McMahon-Pratt,
John Walker,
Jurgen Bernhagen,
Elias Lolis,
Richard Bucala
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ABSTRACT: Parasitic organisms have evolved specialized strategies to evade immune defense mechanisms. We describe herein an ortholog of the cytokine, macrophage migration inhibitory factor (MIF), which is produced by the obligate intracellular parasite, Leishmania major. The Leishmania MIF protein, Lm1740MIF, shows significant structural homology with human MIF as revealed by a high-resolution x-ray crystal structure (1.03 A). Differences between the two proteins in the N-terminal tautomerization site are evident, and we provide evidence for the selective, species-specific inhibition of MIF by small-molecule antagonists that target this site. Lm1740MIF shows significant binding interaction with the MIF receptor, CD74 (K(d) = 2.9 x 10(-8) M). Like its mammalian counterpart, Lm1740MIF induces ERK1/2 MAP kinase activation in a CD74-dependent manner and inhibits the activation-induced apoptosis of macrophages. The ability of Lm1740MIF to inhibit apoptosis may facilitate the persistence of Leishmania within the macrophage and contribute to its evasion from immune destruction.
The Journal of Immunology 06/2008; 180(12):8250-61. · 5.79 Impact Factor
