652: Fetal host response to gram negative bacteria involves the novel Toll-like receptor-4 (TLR4) chaperone protein, soluble myeloid differentiation factor (SMD2)

ABSTRACT It is not clear how the host initially recognizes and responds to infection by gram-negative pathogenic Brucella spp. It was previously shown (D. S. Weiss, B. Raupach, K. Takeda, S. Akira, and A. Zychlinsky, J. Immunol. 172:4463-4469, 2004) that the early macrophage response against gram-negative bacteria is mediated by Toll-like receptor 4 (TLR4), which signals in response to lipopolysaccharide (LPS). Brucella, however, has a noncanonical LPS which does not have potent immunostimulatory activity. We evaluated the kinetics of TLR4 activation and the cytokine response in murine macrophages after Brucella infection. We found that during infection of macrophages, Brucella avoids activation of TLR4 at 6 h but activates TLR4, TLR2, and myeloid differentiation factor 88 (MyD88) at 24 h postinfection. Interestingly, even though its activation is delayed, MyD88 is important for host defense against Brucella infection in vivo, since MyD88−/− mice do not clear the bacteria as efficiently as wild-type, TLR4−/−, TLR2−/−, or TLR4/TLR2−/− mice.

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High mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling promotes progression of gastric cancer

Tumor Biology ◽

10.1177/1010428317694312 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769431 ◽

Cited By ~ 5

Author(s):

Yanqiu Yue ◽

Tao Zhou ◽

Yanjing Gao ◽

Zongli Zhang ◽

Li Li ◽

...

Keyword(s):

Gastric Cancer ◽

Nuclear Factor Kappa B ◽

High Mobility ◽

High Mobility Group ◽

Myeloid Differentiation ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Differentiation Factor ◽

Myeloid Differentiation Factor 88 ◽

Myeloid Differentiation Factor

High mobility group box 1 and toll-like receptor 4/myeloid differentiation factor 88 signaling pathway have been indicated to have oncogenic effects in many cancers. However, the role of high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling pathway in the development of gastric cancer remains unclear. In this study, we demonstrated that high mobility group box 1, toll-like receptor 4, and myeloid differentiation factor 88 were overexpressed in gastric cancer tumors compared with the adjacent non-tumor tissues. The overexpression of high mobility group box 1, toll-like receptor 4, and myeloid differentiation factor 88 were correlated with tumor-node-metastasis stage (p = 0.0068, p = 0.0063, p = 0.0173) and lymph node metastasis (p = 0.0272, p = 0.0382, and p = 0.0495). Furthermore, we observed that knockdown of high mobility group box 1 by high mobility group box 1-small interfering RNA suppressed the expression of toll-like receptor 4 and myeloid differentiation factor 88. Blockage of high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling by high mobility group box 1-small interfering RNA resulted in elevation of apoptotic ratio and inhibition of cell growth, migration, and invasion by upregulating Bax expression and downregulating Bcl-2, matrix metalloproteinase-2, nuclear factor kappa B/p65 expression, and the nuclear translocation of nuclear factor kappa B/p65 in gastric cancer cells. Our findings suggest that high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling pathway may contribute to the development and progression of gastric cancer via the nuclear factor kappa B pathway and it also represents a novel potential therapeutic target for gastric cancer.

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