Myeloid differentiation 2 as a therapeutic target of inflammatory disorders

Park, Sun Hong; Kim, Nam Doo; Cho, Jungsook; Lee, Chong-Kil; Han, Sang‐Bae; Kim, Youngsoo

doi:10.1016/j.pharmthera.2011.11.001

Cited by 60 publications

(59 citation statements)

References 66 publications

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“…LPS is presented to TLR4/MD2 complex via the LPS-binding protein and CD14 . MD2 recognizes the lipid A domain of LPS, leading to the formation of the TLR4/MD2/LPS complex and activation of the downstream cellular response (Park et al, 2012;Oblak and Jerala, 2015). Both TLR4 and MD2 are essential for the LPS-induced inflammatory response and sepsis.…”

Section: Md2 As Therapeutic Target For Inflammatory Disordersmentioning

confidence: 99%

“…Subsequent TLR4 activation leads to the recruitment of myeloid differentiation primary-response gene 88 (MyD88), activating downstream nuclear factor (NF)-kB and mitogen-activated protein kinase (MAPK) pathways. It is well known that LPS from Gram-negative bacteria is a potent stimulant of the immune response (Rossol et al, 2011), and the activation of the NF-kB and MAPK pathways induces the upregulation and increased expression of proinflammatory genes, contributing to multiple organ dysfunction and systemic inflammatory response syndrome (Park et al, 2012;Cighetti et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, rather than TLR4, it is MD2 that recognizes the lipid A moiety of LPS, and MD2 is absolutely required to trigger LPS-induced TLR4 activity and primarily responsible for determining the specificity of different LPS chemotypes (Park et al, 2012). Since MD2 plays a critical role in LPS recognition, increasing studies reveal that MD2 can be the potential therapeutic target of acute inflammatory disorders, including sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2

Wang

Shan

Dai

et al. 2015

J Pharmacol Exp Ther

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Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various proinflammatory cytokines, remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through the myeloid differentiation protein 2 (MD2) and Toll-like receptor 4 (TLR4) complex, increase the production of inflammatory mediators. Our previous studies have found that a curcumin analog, L48H37 [1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)piperidin-4-one], was able to inhibit LPS-induced inflammation, particularly tumor necrosis factor a and interleukin 6 production and gene expression in mouse macrophages. In this study, a series of biochemical experiments demonstrate L48H37 specifically targets MD2 and inhibits the interaction and signaling transduction of LPS-TLR4/ MD2. L48H37 binds to the hydrophobic region of MD2 pocket and forms hydrogen bond interactions with Arg 90 and Tyr 102. Subsequently, L48H37 was shown to suppress LPS-induced mitogenactivated protein kinase phosphorylation and nuclear factor kB activation in macrophages; it also dose dependently inhibits the cytokine expression in macrophages and human peripheral blood mononuclear cells stimulated by LPS. In LPS-induced septic mice, both pretreatment and treatment with L48H37 significantly improved survival and protected lung injury. Taken together, this work identified a new MD2 specific inhibitor, L48H37, as a potential candidate in the treatment of sepsis.

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Section: Md2 As Therapeutic Target For Inflammatory Disordersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2

Wang

Shan

Dai

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

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“…In addition, MD-2 knockout mice do not respond to LPS and survive against endotoxic shock (48). Hence MD-2 is logical target for pharmacological intervention against triggering of TLR4 signaling (49, 50). As LPS recognition is the first step of the signaling pathway, inhibiting this process could be an efficient way to suppress inflammatory responses before the signal has been transmitted into the downstream pathways.…”

Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Myeloid Differentiation Protein-2 Inhibits TLR4-Mediated Lung Inflammation

Tumurkhuu

Dagvadorj

Jones

et al. 2015

The Journal of Immunology

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We previously identified a novel alternatively spliced isoform of human myeloid differentiation protein-2 (MD-2s) that competitively inhibits binding of MD-2 to TLR4 in vitro. Here we investigated the protective role of MD-2s in LPS-induced acute lung injury by delivering intracheally (i.t.) an adenovirus construct that expressed MD-2s (Ad-MD-2s). After adenovirus-mediated gene transfer, MD-2s was strongly expressed in lung epithelial cells and readily detected in bronchoalveolar lavage fluid (BALF). Compared to Ad-EV control mice, Ad-MD-2s delivery resulted in significantly less LPS-induced inflammation in the lungs, including less protein leakage, cell recruitment, and expression of proinflammatory cytokines and chemokines, such as IL-6, KC, and MIP-2. BALF from Ad-MD-2s mice transferred into lungs of naive mice before i.t. LPS challenge diminished pro-inflammatory cytokine levels. As house dust mite (HDM) sensitization is dependent on TLR4 and HDM Der p 2, a structural homolog of MD-2, we also investigated the effect of MD-2s on house dust mite (HDM)-induced allergic airway inflammation. Ad-MD-2s given before HDM sensitization significantly inhibited subsequent allergic airway inflammation after HDM challenge, including reductions in eosinophils, goblet cell hyperplasia, and IL-5 levels. Our study indicates that the alternatively spliced short isoform of human MD-2 could be a potential therapeutic candidate to treat human diseases induced or exacerbated by TLR4 signaling, such as Gram-negative bacterial endotoxin-induced lung injury and house dust mite-triggered allergic lung inflammation.

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“…Unfortunately, the phase III study of eritoran showed no significant differences between the treatment and placebo groups (38). Recently, natural and synthetic chemicals that are unrelated to the structure of bacterial lipid A have also been reported to be MD-2-directed LPS antagonists (39). The mechanisms of binding the MD-2 pocket can be divided into three general types: 1) competition for entry into the MD-2 pocket (e.g., bis-ANS [1-anilinonaphthalene 8-sulfonate] and paclitaxel), 2) covalent interaction with the Cys133 residue within the MD-2 pocket (e.g., N-pyrene maleimide, auranofin, JTT-705), and 3) linear alignment at the mouth of the bottom interior portion of the pocket (e.g., JSH, curcumin, xanthohumol, isoxanthohumol).…”

Section: Discussionmentioning

confidence: 99%

Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties

Chen

Shiau

Wang

et al. 2014

The Journal of Immunology

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TLR4, a membrane receptor that functions in complex with its accessory protein myeloid differentiation factor-2 (MD-2), is a therapeutic target for bacterial infections. Taiwanofungus camphoratus is highly valued as a medicinal mushroom for cancer, hypertension, and inflammation in traditional medicine. Zhankuic acid A (ZAA) is the major pharmacologically active compound of T. camphoratus. The mechanism of action of T. camphoratus or ZAA has not been fully elucidated. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two Abs against MD-2 were used to verify the MD-2/ZAA interaction. The inflammation and survival of the mice pretreated with ZAA and injected with LPS were monitored. The modeling structure shows that ZAA binds the MD-2 hydrophobic pocket exclusively via specific molecular recognition; the contact interface is dominated by hydrophobic interactions. Binding of ZAA to MD-2 reduced Ab recognition to native MD-2, similar to the effect of LPS binding. Furthermore, ZAA significantly ameliorated LPS-induced endotoxemia and Salmonella-induced diarrhea in mice. Our results suggest that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, may be a potential therapeutic agent for gram-negative bacterial infections.

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Myeloid differentiation 2 as a therapeutic target of inflammatory disorders

Cited by 60 publications

References 66 publications

Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2

Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2

Alternatively Spliced Myeloid Differentiation Protein-2 Inhibits TLR4-Mediated Lung Inflammation

Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties

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