Related Experiment Video
Updated: Aug 9, 2026
Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms
Published on: May 29, 2020
Agonistic antibody to TLR4/MD-2 protects mice from acute lethal hepatitis induced by TNF-alpha
Sachiko Akashi-Takamura1, Takahisa Furuta, Koichiro Takahashi
1Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Japan.
Abstract:
LPS is recognized by a heterodimer consisting of TLR4 and its coreceptor MD-2. LPS signal causes excessive inflammation and tissue damage. In this study, we show that a mAb to TLR4/MD-2 protected mice from acute lethal hepatitis caused by LPS/d-galactosamine. The protective effect of the mAb was not due to inhibition of LPS response, because serum TNF-alpha, which was induced by LPS and caused lethal hepatitis, was 10 times up-regulated by the mAb pretreatment. Moreover, this mAb induced antiapoptotic genes in liver in a TLR4/MD-2-dependent manner. These results demonstrated that an agonistic mAb to TLR4/MD-2 protected mice from LPS/d-galactosamine-induced acute lethal hepatitis by delivering a protective signal activating NF-kappaB through TLR4/MD-2.
Insights
A novel antibody targeting Toll-like receptor 4/MD-2 (TLR4/MD-2) protected mice from lethal hepatitis. This antibody activated protective signals, rather than inhibiting the inflammatory response, highlighting a new therapeutic strategy for LPS-induced liver damage.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Lipopolysaccharide (LPS) recognition by Toll-like receptor 4 (TLR4) and its coreceptor MD-2 triggers excessive inflammation and tissue damage.
- LPS-induced signaling can lead to severe conditions such as acute lethal hepatitis.
Purpose of the Study:
- To investigate the protective potential of a monoclonal antibody (mAb) targeting the TLR4/MD-2 complex against LPS/d-galactosamine-induced acute lethal hepatitis in mice.
- To elucidate the mechanism underlying the protective effect of the anti-TLR4/MD-2 mAb.
Main Methods:
- Administration of an agonistic mAb targeting TLR4/MD-2 to mice challenged with LPS/d-galactosamine.
- Measurement of serum TNF-alpha levels to assess inflammatory response.
- Analysis of antiapoptotic gene expression in the liver.
- Investigation of NF-kappaB activation pathway.
Main Results:
- The anti-TLR4/MD-2 mAb conferred significant protection against LPS/d-galactosamine-induced acute lethal hepatitis.
- Contrary to expectations, the mAb upregulated serum TNF-alpha, indicating it did not inhibit the LPS response.
- The mAb induced antiapoptotic genes in the liver in a TLR4/MD-2-dependent manner.
- The protective effect was mediated by activation of NF-kappaB signaling through TLR4/MD-2.
Conclusions:
- An agonistic mAb targeting TLR4/MD-2 offers protection against LPS-induced acute lethal hepatitis.
- The protective mechanism involves the induction of a pro-survival signal via TLR4/MD-2, leading to NF-kappaB activation and antiapoptotic gene expression.
- This study presents a novel therapeutic approach for managing LPS-mediated liver injury by modulating TLR4/MD-2 signaling.
