Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage.
Previously, we have shown that primary afferent neurons are necessary for disease activity in immune-mediated liver injury in mice. These nerve fibers are detectable by substance P (SP) immunocytochemistry in the portal tract of rodent liver. Antagonists of the neurokinin-1 receptor (NK-1R), which is the prime receptor of SP, prevented liver damage by suppressing the synthesis of proinflammatory cytokines. Here, we investigated the influence of primary afferent nerve fibers, SP, and NK-1 receptor antagonists on hepatocyte apoptosis in vivo induced by administration of activating anti-CD95 monoclonal antibody (mAb) to mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment prevented CD95-mediated activation of caspase-3, measured as enzymatic activity in liver homogenates or by demonstration of hepatocellular immunoreactivity for active caspase-3 in liver slices, and liver damage. This effect was reversed by administration of SP to anti-CD95 mAb-treated mice depleted from primary afferent neurons. The presence of the NK-1R on mouse hepatocytes was demonstrated by immunocytochemistry and flow cytometry. Intraperitoneal pretreatment with the NK-1 receptor antagonists (2S,3S)-cis-2-(diphenylmethyl)-N-([2-methoxyphenyl]-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) or (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperadine (L-733,060) dose dependently protected mice from CD95-mediated liver injury. Similar results were obtained when apoptotic liver damage was induced by administration of tumor necrosis factor-alpha to d-galactosamine-sensitized mice. In conclusion, SP, probably by binding to its receptor on hepatocytes, might aggravate apoptotic signals in these cells. Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent liver cell apoptosis in vivo, they might be suitable drugs for treatment of immune-mediated liver disease.
Bang
Renate
R
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.
Biburger
Markus
M
Neuhuber
Winfried L
WL
Tiegs
Gisa
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis; D002211:Capsaicin / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000502:physiology; D020011:Protective Agents / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D019014:fas Receptor / Q000276:immunology / Q000633:toxicity
D000911:Antibodies, Monoclonal; D064729:Neurokinin-1 Receptor Antagonists; D020011:Protective Agents; D018040:Receptors, Neurokinin-1; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D002211:Capsaicin