An MD2-derived peptide promotes LPS aggregation, facilitates its internalization in THP-1 cells, and inhibits LPS-induced pro-inflammatory responses

Tandon, Anshika; Harioudh, Munesh Kumar; Ishrat, Nayab; Tripathi, Amit Kumar; Srivastava, Saurabh; Ghosh, Jimut Kanti

doi:10.1007/s00018-017-2735-2

Cited by 17 publications

(26 citation statements)

References 48 publications

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“…The first signaling event of these pathways is NF-κB activation through TLR4 activation [24]. To investigate how the individual CD14, TLR4, and MD2 proteins contribute to the responses of cells to CL, we used the HEK transfection model where we can control which protein (including from different species) may be added to the cells and their contribution to CL activation of Nf-κB [21, 30, 31]. We transfected HEK293 cells with human or murine CD14 and MD2 with or without TLR4 and incubated them with saturated CLs for 6 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4

Pizzuto

Lonez

Baroja‐Mazo

et al. 2019

Cell. Mol. Life Sci.

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Cardiolipins (CLs) are tetra-acylated diphosphatidylglycerols found in bacteria, yeast, plants, and animals. In healthy mammals, CLs are unsaturated, whereas saturated CLs are found in blood cells from Barth syndrome patients and in some Gram-positive bacteria. Here, we show that unsaturated but not saturated CLs block LPS-induced NF-κB activation, TNF-α and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-α and IL-1β release in human blood mononuclear cells. Using HEK293 cells transfected with Toll-like receptor 4 (TLR4) and its co-receptor Myeloid Differentiation 2 (MD2), we demonstrate that unsaturated CLs compete with LPS for binding TLR4/MD2 preventing its activation, whereas saturated CLs are TLR4/MD2 agonists. As a consequence, saturated CLs induce a pro-inflammatory response in macrophages characterized by TNF-α and IP-10 secretion, and activate the alternative NLRP3 inflammasome pathway in human blood-derived monocytes. Thus, we identify that double bonds discriminate between anti- and pro-inflammatory properties of tetra-acylated molecules, providing a rationale for the development of TLR4 activators and inhibitors for use as vaccine adjuvants or in the treatment of TLR4-related diseases. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00018-019-03113-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4

Pizzuto

Lonez

Baroja‐Mazo

et al. 2019

Cell. Mol. Life Sci.

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“…Previous studies have found that the MD2 and TLR4 signaling pathways play an important role in acute inflammation (23,24). Our previous research also identified a crucial role of these pathways in some chronic diseases, such as diabetes (25,26), obesity (27,28), etc.…”

Section: Discussionmentioning

confidence: 61%

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

Fang

et al. 2021

J Gastrointest Oncol

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Background: The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness.However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC).Methods: Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative realtime PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules.Results: MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing.Conclusions: Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.

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“…MD2 has been well recognized as an indispensable accessory protein linking LPS and TLR4 [15,16], and targeting MD2 could effectively attenuate LPS-induced inflammatory response and sepsis [13,17,18]. Recently, we further prove that MD2 could also be an attractive therapeutic target for the treatment of many non-infectious chronic inflammatory diseases, including cardiac/kidney injuries induced by hypertension [19], obesity [20,21], and diabetes [22].…”

Section: Discussionmentioning

confidence: 89%

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

Rajamanickam¹,

Yan²,

Xu³

et al. 2020

Int. J. Biol. Sci.

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Toll-like receptor (TLR) signaling is an emerging pathway in tumor cell invasion and metastasis. Myeloid differentiation protein-2 (MD2) contributes to ligand recognition and activation of TLRs in response to exogenous microbial insults or endogenous agents. We hypothesized that blocking MD2 using a specific inhibitor would prevent TLR4-mediated inflammatory responses and metastatic cancer growth. Here, we report that a MD2 inhibitor, L6H21, inhibited migration and invasion of LPS-activated colon cancer CT26.WT cells. These activities were accompanied by inhibition of nuclear factor-κB (NF-κB) activation, and thereby inhibition of the production of pro-inflammatory cytokines and adhesive molecules in colon cancer cells. Furthermore, L6H21 inhibited CT26.WT metastasis to the lung in BALB/c mice as well as suppressed colitis-induced colon cancer induced by azoxymethane/dextran sulfate sodium (AOM/DSS). Taken together, our results demonstrated that L6H21 suppressed tumor invasion and metastasis through blocking TLR4-MD2/NF-κB signaling axis. These findings reveal that inhibition of MD2 may be an important target for the development of colon cancer therapies.

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An MD2-derived peptide promotes LPS aggregation, facilitates its internalization in THP-1 cells, and inhibits LPS-induced pro-inflammatory responses

Cited by 17 publications

References 48 publications

Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4

Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

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