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Thalidomide protects mice against LPS-induced shock
A L Moreira1, J Wang, E N Sarno
1Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021, USA. moreira@rockvax.rockefeller.edu
Summary
Thalidomide significantly reduces tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced shock mouse models. This immunomodulatory effect increases survival rates, demonstrating thalidomide
Area of Science:
- Immunology
- Pharmacology
- Pathophysiology
Background:
- Tumor necrosis factor-alpha (TNF-alpha) is a key mediator in the pathophysiology of endotoxic shock.
- Thalidomide is known to selectively inhibit TNF-alpha production in vitro.
- Lipopolysaccharide (LPS) is a potent endotoxin that triggers a severe inflammatory response.
Purpose of the Study:
- To investigate the in vivo effects of thalidomide on cytokine production and survival in a mouse model of LPS-induced endotoxic shock.
- To determine the impact of thalidomide on TNF-alpha, IL-6, IL-10, IL-1 beta, GM-CSF, and IFN-gamma levels following LPS challenge.
- To assess the protective efficacy of thalidomide against lethal doses of LPS.
Main Methods:
- Mice were challenged with varying doses of LPS (100-350 micrograms) to induce endotoxic shock.
- Thalidomide (200 mg/kg) was administered prior to LPS challenge.
- Serum cytokine levels (TNF-alpha, IL-6, IL-10, IL-1 beta, GM-CSF, IFN-gamma) and splenic TNF-alpha mRNA expression were measured.
- The median lethal dose (LD50) of LPS was determined in thalidomide-treated and untreated mice.
Main Results:
- Thalidomide administration significantly reduced serum TNF-alpha levels by 93% and splenic TNF-alpha mRNA expression by 70% in a dose-dependent manner.
- Serum IL-6 levels were inhibited by 50%, while IL-10 levels showed a two-fold increase.
- Thalidomide treatment did not affect the production of GM-CSF, IL-1 beta, or IFN-gamma.
- The LD50 of LPS increased from 150 micrograms to 300 micrograms in thalidomide-pre-treated mice, indicating enhanced survival.
Conclusions:
- Thalidomide effectively modulates the cytokine storm associated with LPS-induced endotoxic shock in vivo.
- By inhibiting key pro-inflammatory cytokines like TNF-alpha and IL-6, thalidomide confers significant protection against lethal endotoxemia.
- These findings highlight thalidomide's therapeutic potential in managing conditions characterized by excessive cytokine production.