Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock (Nat Med, 2007, 13:1042-1049)

報告日期: 2007/11/06
報告時間: 15:10/16:00
報告學生: 呂秀菱
講評老師: 凌 斌
附件下載:

Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock

 

Speaker: Shiou-Ling Lu   

Commentator: Dr. Pin Ling

Time: 15:10 ~ 16:00

Place: 602

 

Abstract:

    Inflammatory response can be efficiently induced by endotoxin, or lipopolysaccharide (LPS), which is a major component in the Gram-negative bacteria cell wall. LPS induces downstream signaling, which leads to activation of transcription factor NF-kB and sequentially cytokine genes expression through binding to LPS-binding complex, including CD14, Toll-like receptor 4 (TLR4) and myeloid differentiation factor-2 (MD2), in phagocytes. Myeloid-related protein-8 (Mrp8, S100A8) and Mrp14 (S100A9) are two major cytoplasmic proteins of phagocytes, and play significant roles in the pathogenesis of sepsis1. However, the exact extracellular functions of these proteins are still unclear. Here, the authors2 demonstrated that LPS-induced shock and inflammatory cytokine TNF-a were decreased in Mrp14-/- mice lack of Mrp8-Mrp14 complex. In in vitro studies, they showed that LPS-induced signaling mediators, such as MAP kinase, TNF-a, MIP-2, and gp91phox, were decreased at transcriptional levels. Reduced induction of TNF-a by LPS was due to diminished activation of NF-kB in Mrp14-/- phagocytes. Those effects could be reversed by compensating with Mrp8-Mrp14 complex. They also found that Mrp8 is the active component of the Mrp8-Mrp14 complex, and Mrp14 modulates the activity of Mrp8. Mrp8-Mrp14 complex could induce translocation of MyD88 and hyperphosphorylation of IRAK-1 involved in TLR4-dependent signaling pathway. Therefore, the authors concluded that Mrp8-Mrp14 complex is an endogenous ligand of TLR4 that amplifies LPS effects and promote lethality during septic shock.

 

References:

1.          Roth, J. et al., Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. Trends Immunol. 24, 155-8, 2003

2.          Vogl, T. et al., Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat. Med. 13, 1042-9, 2007