The neuropeptide calcitonin gene-related peptide (CGRP) prevents inflammatory liver injury in mice.
OBJECTIVE
Calcitonin gene-related peptide (CGRP) is a potent vasodilator and supposed to be responsible for neurogenic inflammation involved in migraine. Its role in inflammatory diseases of other organs is controversial and poorly investigated regarding liver inflammation, although the organ is innervated by CGRP containing primary sensory nerve fibers.


METHODS
Male Balb/c and IL-10(-/-) mice were pretreated with either alphaCGRP or the CGRP receptor antagonists CGRP(8-37) or BIBN4096BS. Immune-mediated liver injury was induced by administration of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNFalpha) to galactosamine (GalN)-sensitized mice and evaluated by serum transaminase activities and cytokine levels. Furthermore, intrahepatic CGRP receptor expression and hepatic CGRP concentrations were examined.


RESULTS
CGRP receptor 1 was expressed by immune cells and hepatocytes in human and murine liver. During liver injury CGRP receptor expression was increased whereas hepatic CGRP concentrations concomitantly decreased. While CGRP receptor antagonists failed to affect liver damage, pretreatment with alphaCGRP protected mice from GalN/LPS-induced liver injury by suppression of the pro-inflammatory cytokine response independently from IL-10 but related to the induction of the transcriptional repressor inducible cAMP early repressor (ICER). In contrast, alphaCGRP failed to protect against GalN/TNFalpha-induced liver failure.


CONCLUSIONS
In the liver, CGRP exerts anti-inflammatory properties, which are characterized by a reduced production of pro-inflammatory cytokines.
Kroeger
Irena
I
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.
Erhardt
Annette
A
Abt
Dominik
D
Fischer
Michael
M
Biburger
Markus
M
Rau
Thomas
T
Neuhuber
Winfried L
WL
Tiegs
Gisa
G
D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology* / Q000502:physiology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005688:Galactosamine / Q000276:immunology; D006505:Hepatitis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007114:Immunization; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000293:injuries; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018015:Receptors, Calcitonin Gene-Related Peptide; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005688:Galactosamine; D015740:Calcitonin Gene-Related Peptide