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[Cathepsin B in Hepatic Kupffer Cells Regulates Activation of TLR4-independent Inflammatory Pathways in Mice With Lipopolysaccharide-Induced Sepsis]

[Cathepsin B in Hepatic Kupffer Cells Regulates Activation of TLR4-independent Inflammatory Pathways in Mice With Lipopolysaccharide-Induced Sepsis]

Panpan Feng, Wei Zhu, Nan Chen, Peizhi Li, Kun He, Jianping Gong

Nan Fang Yi Ke Da Xue Xue Bao. 2018 Dec 30;38(12):1465-1471.

PMID: 30613015

Abstract:

Objective:
To investigate the role of cathepsin B in hepatic Kupffer cells (KCs) in activating Toll-like receptor 4(TLR- 4)-independent inflammatory pathways in mice with lipopolysaccharide (LPS)-induced sepsis.
Methods:
Eighteen wild-type (WT) mice and 18 TLR4-knockout (TLR4-/-) mice were both divided into 3 groups for intraperitoneal injections of a lethal dose (54 mg/kg) of LPS, LPS and CA-074(a cathepsin B inhibitor), or normal saline, and the survival of the mice were observed. Another 36 WT mice and 36 TLR4-/-mice were also divided into 3 groups and subjected to intraperitoneal injections of normal saline, 20 mg/kg LPS, or LPS with CA-074 pretreatment.After the treatments, KCs were collected from the mice for assessing the protein level and activity of cathepsin B.The histopathological changes of the liver were observed with HE staining, and the serum levels of IL-1α, IL-1β, TNF-α and IL-18 were detected.
Results:
Compared with the WT mice,TLR4-/-mice receiving the lethal dose of LPS had significantly longer survival time (up to 84 h) after the injection,but were still unable to fully resist LPS challenge.CA-074 pretreatment prolonged the survival time of WT mice and TLR4-/-mice to 60 h and 132 h,respectively.In the mouse models of sepsis,20 mg/kg LPS induced significantly enhanced activity of cathepsin B without affecting its expression level in the KCs (P<0.05) and increased the serum levels of the inflammatory cytokines.CA-074 pretreatment of the mice obviously lessened the detrimental effects of LPS in TLR4-/-mice by significantly lowering cathepsin B activity in the KCs,alleviating hepatocyte apoptosis and reducing the serum levels of inflammatory cytokines.
Conclusions:
Cathepsin B plays an important role in activating TLR4-independent inflammatory pathways in mice with LPS-induced sepsis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP134448105	CA-074		134448-10-5	Price

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