Novel Anti-inflammatory Activity of Epoxyazadiradione against Macrophage Migration Inhibitory Factor

Alam, Athar; Haldar, Saikat; Thulasiram, Hirekodathakallu V.; Kumar, Rahul; Goyal, Manish; Iqbal, Mohammad; Pal, Chiranjib; Dey, Sumanta; Bindu, Samik; Sarkar, Souvik; Pal, Uttam; Maiti, Nakul C.; Bandyopadhyay, Uday

doi:10.1074/jbc.m112.341321

Cited by 90 publications

(58 citation statements)

References 87 publications

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“…The binding of EhMIF to host macrophages suggested that EhMIF might be capable of interfering with or modulating macrophage activity. MIF homologs have been shown to promote inflammation by enhancing proinflammatory cytokine production (9,11,16,17). For cytokine assays, we used endotoxin-free recombinant EhMIF (Ͻ1 pg LPS/g protein).…”

Section: Resultsmentioning

confidence: 99%

“…Proinflammatory functions include the following: (i) MIF induces the secretion of inflammatory mediators, such as interleukin-6 (IL-6); (ii) MIF enhances TNF-␣ production by lipopolysaccharide (LPS)-stimulated immune cells; and (iii) MIF can counterregulate the anti-inflammatory activities of glucocorticoids (9)(10)(11)(12)(13)(14)(15)(16)(17). Many of the inflammatory effects of MIF are initiated via direct binding to its cell surface receptor, CD74 (18).…”

mentioning

confidence: 99%

“…Protozoan MIF homologs have demonstrated biological activity similar to that of mammalian MIF. For example, Plasmodium MIF was shown to enhance TNF-␣ secretion by immune cells after stimulation with LPS (11,16). The presence of a MIF homolog in E. histolytica implies a potential mechanism that may contribute to the proinflammatory host response that occurs during infection.…”

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confidence: 99%

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The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

et al. 2014

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bThe host inflammatory response contributes to the tissue damage that occurs during amebic colitis, with tumor necrosis factor alpha (TNF-␣) being a key mediator of the gut inflammation observed. Mammalian macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the exacerbation of a wide range of inflammatory diseases, including colitis. We identified a MIF gene homolog in the Entamoeba histolytica genome, raising the question of whether E. histolytica MIF (EhMIF) has proinflammatory activity similar to that of mammalian MIF. In this report, we describe the first functional characterization of EhMIF. Antibodies were prepared against recombinantly expressed EhMIF and used to demonstrate that EhMIF is expressed as a 12-kDa protein localized to the cytoplasm of trophozoites. In a manner similar to that of mammalian MIF, EhMIF interacted with the MIF receptor CD74 and bound to macrophages. EhMIF induced interleukin-6 (IL-6) production. In addition, EhMIF enhanced TNF-␣ secretion by amplifying TNF-␣ production by lipopolysaccharide (LPS)-stimulated macrophages and by inhibiting the glucocorticoid-mediated suppression of TNF-␣ secretion. EhMIF was expressed during human infection, as evidenced by the presence of anti-EhMIF antibodies in the sera of children living in an area where E. histolytica infection is endemic. Anti-EhMIF antibodies did not cross-react with human MIF. The ability of EhMIF to modulate host macrophage function may promote an exaggerated proinflammatory immune response and contribute to the tissue damage seen in amebic colitis.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

et al. 2014

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“…Prior to this report, no such tetranortetracyclic triterpenoid was reported in the literature, although a few such instances have been noted in the case of pentacyclic triterpenoids [13] [14]. The 1 H-NMR spectrum exhibited five Me singlets at d(H) 0.99, 1.17, 1.24, 1.28, and 1.40, implying that the tetracyclic skeleton is intact and not cleaved as observed in nimbolin B or nimbin [12]. ), and the compound was named nimbolicidin.…”

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confidence: 74%

Two New Degraded Triterpenoids and a Novel seco‐Norabietane Diterpene from the Root Bark of Azadirachta indica

Dilshad

Siddiqui

Faizi

2015

Helvetica Chimica Acta

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Three new compounds, the degraded ring C‐seco‐tetranortriterpenoid nimbolicidin (1), the degraded hexanortriterpenoid nimbocin (2), and the seco‐norabietane diterpene nimbocinin (3), were isolated from the root bark of Azadirachta indica A.Juss. Compound 1 is O‐bearing both at C(28) and C(29), which has been hitherto unreported in tetranortriterpenoids; 2 represents the first hexanortriterpenoid with a truncated apotirucallane (or apoeuphane) skeleton; 3 is an unprecedented seco‐norabietane. Spectroscopic data and chemical transformations of these compounds provided their complete structures.

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“…A number of these inhibitors have also been proven beneficial for therapeutic efficacy in MIF-associated diseases (24,40–42). In the present study, inhibition of dopachrome tautomerization was performed to assess inhibition of MIF tautomerase activity mediated by HuScFv.…”

Section: Discussionmentioning

confidence: 99%

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

Tarasuk

Poungpair

Ungsupravate

et al. 2014

International Journal of Molecular Medicine

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Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, secreted from a variety of immune cells, that regulates innate and adaptive immune responses. Elevation of MIF levels in plasma correlates with the severity of inflammatory diseases in humans. Inhibition of MIF or its tautomerase activity ameliorates disease severity by reducing inflammatory responses. In this study, the human single-chain variable fragment (HuScFv) antibody specific to MIF was selected from the human antibody phage display library by using purified recombinant full-length human MIF (rMIF) as the target antigen. Monoclonal HuScFv was produced from phage-transformed bacteria and tested for their binding activities to rMIF by indirect enzyme-linked immunosorbent assay as well as to native MIF by western blot analysis and immunofluorescence assay. The HuScFv with highest binding signal to rMIF also inhibited the tautomerase activities of both rMIF and native MIF in human monoblastic leukemia (U937) cells in a dose-dependent manner. Mimotope searching and molecular docking concordantly demonstrated that the HuScFv interacted with Lys32 and Ile64 in the MIF tautomerase active site. To the best of our knowledge, this is the first study to focus on MIF-specific fully-human antibody fragment with a tautomerase-inhibitory effect that has potential to be developed as anti-inflammatory biomolecules for human use.

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Novel Anti-inflammatory Activity of Epoxyazadiradione against Macrophage Migration Inhibitory Factor

Cited by 90 publications

References 87 publications

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

Two New Degraded Triterpenoids and a Novel seco‐Norabietane Diterpene from the Root Bark of Azadirachta indica

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

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