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Tumor necrosis factor production in the perfused mouse liver and its pharmacological modulation by methylxanthines
M Leist1, S Auer-Barth, A Wendel
1Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
Abstract:
The liver contains the largest pool of cytokine-producing macrophages in the body and may therefore play an important role in the development and outcome of systemic inflammatory response syndromes. Therefore, we investigated the tumor necrosis factor-alpha (TNF) releasing capacity of the in situ perfused mouse liver and its modulation by methylxanthines, i.e., by a class of well-established inflammatory cytokine-suppressing drugs. We have shown that pretreatment of mice with either lipopolysaccharide or TNF elicited a dose-dependent TNF release into the perfusate which was inhibited by in vivo pretreatment of mice with pentoxifylline or A-802715 [1-(5-hydroxy-5-methyl)hexyl-3-methyl-7-propylxanthin]. Infusion of these methylxanthines into livers from mice pretreated with lipopolysaccharide or TNF also inhibited TNF release in an immediate and reversible way even after TNF production had been initiated. The inhibitory effect of methylxanthines was prevented by pretreatment of mice with the adenylate cyclase inhibitor dideoxyadenosine, suggesting upregulation of the cyclic adenosine monophosphate system as a possible mechanism of action of these drugs. Our findings demonstrate that the liver is a potent cytokine producer and identify it as one of the target organs of methylxanthines or other phosphodiesterase inhibitors in murine models of shock and inflammatory liver failure.
Insights
The liver releases tumor necrosis factor-alpha (TNF), a key inflammatory cytokine. Methylxanthines effectively suppress this liver-derived TNF release, suggesting their therapeutic potential in inflammatory conditions.
Area of Science:
- Immunology
- Hepatology
- Pharmacology
Background:
- The liver harbors a significant population of cytokine-producing macrophages.
- Macrophages play a crucial role in systemic inflammatory response syndromes.
- Tumor necrosis factor-alpha (TNF) is a key pro-inflammatory cytokine implicated in these syndromes.
Purpose of the Study:
- To investigate the TNF releasing capacity of the ex vivo perfused mouse liver.
- To determine the modulatory effects of methylxanthines on liver-derived TNF production.
- To elucidate the mechanism of action of methylxanthines in suppressing TNF release.
Main Methods:
- Utilized an in situ perfused mouse liver model.
- Administered lipopolysaccharide (LPS) or TNF to induce cytokine release.
- Investigated the effects of methylxanthines (pentoxifylline, A-802715) on TNF release.
- Examined the role of the cyclic adenosine monophosphate (cAMP) pathway using dideoxyadenosine.
Main Results:
- Pretreatment with LPS or TNF induced dose-dependent TNF release from the liver.
- Methylxanthines significantly inhibited TNF release, both preventatively and during ongoing production.
- The inhibitory effect was reversible and dependent on the adenylate cyclase/cAMP system.
- Dideoxyadenosine blocked the suppressive action of methylxanthines.
Conclusions:
- The liver is a major source of TNF and a potential target organ in inflammatory diseases.
- Methylxanthines and other phosphodiesterase inhibitors can suppress liver-derived TNF.
- These findings support the use of methylxanthines in managing inflammatory liver failure and shock.