Kroeger Irena, Erhardt Annette, Abt Dominik, Fischer Michael, Biburger Markus, Rau Thomas, Neuhuber Winfried L, Tiegs Gisa
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.
J Hepatol. 2009 Aug;51(2):342-53. doi: 10.1016/j.jhep.2009.03.022. Epub 2009 May 3.
BACKGROUND/AIMS: 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.
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.
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.
In the liver, CGRP exerts anti-inflammatory properties, which are characterized by a reduced production of pro-inflammatory cytokines.
背景/目的：降钙素基因相关肽（CGRP）是一种强效血管舒张剂，被认为与偏头痛相关的神经源性炎症有关。尽管肝脏受含CGRP的初级感觉神经纤维支配，但其在其他器官炎症性疾病中的作用存在争议，关于肝脏炎症的研究也很少。
对雄性Balb/c和IL-10（-/-）小鼠分别用αCGRP或CGRP受体拮抗剂CGRP（8-37）或BIBN4096BS进行预处理。通过向半乳糖胺（GalN）致敏的小鼠注射脂多糖（LPS）或肿瘤坏死因子-α（TNFα）诱导免疫介导的肝损伤，并通过血清转氨酶活性和细胞因子水平进行评估。此外，检测肝内CGRP受体表达和肝脏CGRP浓度。
CGRP受体1在人和小鼠肝脏的免疫细胞和肝细胞中表达。在肝损伤期间，CGRP受体表达增加，而肝脏CGRP浓度随之降低。虽然CGRP受体拮抗剂未能影响肝损伤，但用αCGRP预处理可通过抑制促炎细胞因子反应保护小鼠免受GalN/LPS诱导的肝损伤，这一作用独立于IL-10，但与转录抑制因子诱导型cAMP早期抑制因子（ICER）的诱导有关。相反，αCGRP未能预防GalN/TNFα诱导的肝衰竭。
在肝脏中，CGRP具有抗炎特性，其特征是促炎细胞因子的产生减少。
