Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells

Yang,Yan; Yan,Ming; Zhang,Haitao; Wang,Xuping

doi:10.3892/etm.2013.1152

Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells

Authors:
- Yan Yang
- Ming Yan
- Haitao Zhang
- Xuping Wang
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Affiliations: Health Examination Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China, Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China, Interventional Center, Jinan Infectious Disease Hospital, Jinan, Shandong 250021, P.R. China, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: June 10, 2013 https://doi.org/10.3892/etm.2013.1152
Pages: 459-464

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Abstract

Studies have indicated that the immune system plays a pivotal role in hepatitis. Substance P (SP) has been shown to modulate the immune response. In order to investigate the role of SP in liver injury and to determine whether it leads to pro-inflammatory signaling, we established a mouse model of hepatic injury induced by concanavalin A (ConA). We also exposed mouse Kupffer cells (KCs) to SP in vitro. Cytokine and SP levels in liver homogenates were detected using enzyme-linked immunosorbent assay (ELISA) and the protective effects of L-703,606 were evaluated through serological and histological assessments. Neurokinin-1 receptor (NK-1R) expression was evaluated by immunofluorescence and quantitative polymerase chain reaction (PCR). The levels of SP, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased in the ConA-treated mice and the levels of ALT and AST were markedly reduced by L-703,606-pretreatment. Liver injury was significantly reduced by treatment with L-703,606. The mouse KCs expressed NK-1R and SP increased NK-1R mRNA expression. Furthermore, NK-1R blockade eliminated the effect of SP on NK-1R mRNA expression. The cytokine levels exhibited a substantial increase in the SP-pretreated KCs compared with the KCs that were cultured in control medium. The interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the L-703,606‑pretreated KCs were significantly lower compared with those in the SP-pretreated KCs. Our study suggests that neurogenic inflammation induced by SP plays an important role in hepatitis. Mouse KCs express NK-1R and SP increases NK-1R mRNA expression. SP enhances IL-6 and TNF-α secretion and an NK-1R antagonist inhibits this secretion.

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1.	Mackay IR: Immunological aspects of chronic active hepatitis. Hepatology. 3:724–728. 1983. View Article : Google Scholar : PubMed/NCBI
2.	Richardson JD and Vasko MR: Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther. 302:839–845. 2002. View Article : Google Scholar : PubMed/NCBI
3.	Sternberg EM: Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol. 6:318–328. 2006. View Article : Google Scholar : PubMed/NCBI
4.	Greco SJ, Corcoran KE, Cho KJ and Rameshwar P: Tachykinins in the emerging immune system: relevance to bone marrow homeostasis and maintenance of hematopoietic stem cells. Front Biosci. 9:1782–1793. 2004. View Article : Google Scholar : PubMed/NCBI
5.	Satake H and Kawada T: Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors. Curr Drug Targets. 7:963–974. 2006. View Article : Google Scholar : PubMed/NCBI
6.	Sterner-Kock A, Braun RK, van der Vliet A, et al: Substance P primes the formation of hydrogen peroxide and nitric oxide in human neutrophils. J Leukoc Biol. 65:834–840. 1999.PubMed/NCBI
7.	Bang R, Biburger M, Neuhuber WL and Tiegs G: Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage. J Pharmacol Exp Ther. 308:1174–1180. 2004. View Article : Google Scholar : PubMed/NCBI
8.	Bang R, Sass G, Kiemer AK, Vollmar AM, Neuhuber WL and Tiegs G: Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. J Pharmacol Exp Ther. 305:31–39. 2003. View Article : Google Scholar : PubMed/NCBI
9.	Kunstle G, Hentze H, Germann PG, et al: Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. Hepatology. 30:1241–1251. 1999. View Article : Google Scholar : PubMed/NCBI
10.	Smedsrød B and Pertoft H: Preparation of pure hepatocytes and reticuloendothelial cells in high yield from a single rat liver by means of Percoll centrifugation and selective adherence. J Leukoc Biol. 38:213–230. 1985.PubMed/NCBI
11.	Lai JP, Douglas SD, Wang YJ and Ho WZ: Real-time reverse transcription-PCR quantitation of substance P receptor (NK-1R) mRNA. Clin Diagn Lab Immunol. 12:537–541. 2005.PubMed/NCBI
12.	Lotz M, Vaughan JH and Carson DA: Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science. 241:1218–1221. 1988. View Article : Google Scholar : PubMed/NCBI
13.	Amoruso A, Bardelli C, Gunella G, Ribichini F and Brunelleschi S: A novel activity for substance P: stimulation of peroxisome proliferator-activated receptor-gamma protein expression in human monocytes and macrophages. Br J Pharmacol. 154:144–152. 2008. View Article : Google Scholar
14.	Dianzani C, Lombardi G, Collino M, Ferrara C, Cassone MC and Fantozzi R: Priming effects of substance P on calcium changes evoked by interleukin-8 in human neutrophils. J Leukoc Biol. 69:1013–1018. 2001.PubMed/NCBI
15.	Ramnath RD and Bhatia M: Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-kappaB. Am J Physiol Gastrointest Liver Physio. 291:G1113–G1119. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Barreto SG, Carati CJ, Schloithe AC, et al: The combination of neurokinin-1 and galanin receptor antagonists ameliorates caerulein-induced acute pancreatitis in mice. Peptides. 31:315–321. 2010. View Article : Google Scholar : PubMed/NCBI
17.	Kaneko Y, Harada M, Kawano T, et al: Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis. J Exp Med. 191:105–114. 2000. View Article : Google Scholar : PubMed/NCBI
18.	Miyazawa Y, Tsutsui H, Mizuhara H, Fujiwara H and Kaneda K: Involvement of intrasinusoidal hemostasis in the development of concanavalin A-induced hepatic injury in mice. Hepatology. 27:497–506. 1998. View Article : Google Scholar : PubMed/NCBI
19.	Neuhuber WL and Tiegs G: Innervation of immune cells: evidence for neuroimmunomodulation in the liver. Anat Rec A Discov Mol Cell Evol Biol. 280:884–892. 2004. View Article : Google Scholar : PubMed/NCBI
20.	Bhatia M, Zhi L, Zhang H, Ng SW and Moore PK: Role of substance P in hydrogen sulfide-induced pulmonary inflammation in mice. Am J Physiol Lung Cell Mol Physiol. 291:L896–L904. 2006. View Article : Google Scholar : PubMed/NCBI
21.	Chauhan VS, Kluttz JM, Bost KL, et al: Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuro-inflammation in a murine model of pneumococcal meningitis. J Immunology. 186:7255–7263. 2011. View Article : Google Scholar : PubMed/NCBI
22.	Vollmar B and Menger MD: The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 89:1269–1339. 2009. View Article : Google Scholar : PubMed/NCBI
23.	Carini R and Albano E: Recent insights on the mechanisms of liver preconditioning. Gastroenterology. 125:1480–1491. 2003. View Article : Google Scholar : PubMed/NCBI
24.	Hildebrand F, Hubbard WJ, Choudhry MA, et al: Kupffer cells and their mediators: the culprits in producing distant organ damage after trauma-hemorrhage. Am J Pathol. 169:784–794. 2006. View Article : Google Scholar : PubMed/NCBI
25.	Solga SF and Diehl AM: Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol. 38:681–687. 2003. View Article : Google Scholar : PubMed/NCBI
26.	Koo DJ, Chaudry IH and Wang P: Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis. J Surg Res. 83:151–157. 1999. View Article : Google Scholar : PubMed/NCBI
27.	Wang YY, Dahle MK, Agren J, et al: Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation. Shock. 25:141–146. 2006. View Article : Google Scholar : PubMed/NCBI
28.	O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP and Shanahan F: The role of substance P in inflammatory disease. J Cell Physiol. 201:167–180. 2004.
29.	Reed KL, Fruin AB, Gower AC, et al: NF-kappaB activation precedes increases in mRNA encoding neurokinin-1 receptor, proinflammatory cytokines, and adhesion molecules in dextran sulfate sodium-induced colitis in rats. Dig Dis Sci. 50:2366–2378. 2005. View Article : Google Scholar
30.	Keeble J, Blades M, Pitzalis C, Castro da Rocha FA and Brain SD: The role of substance P in microvascular responses in murine joint inflammation. Br J Pharmacol. 144:1059–1066. 2005. View Article : Google Scholar : PubMed/NCBI
31.	Karagiannides I, Kokkotou E, Tansky M, et al: Induction of colitis causes inflammatory responses in fat depots: evidence for substance P pathways in human mesenteric preadipocytes. Proc Natl Acad Sci USA. 103:5207–5212. 2006. View Article : Google Scholar : PubMed/NCBI