Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation

Ren,Jun; Meng,Shanshan; Yan,Bingdi; Yu,Jinyan; Liu,Jing

doi:10.3892/mmr.2016.4980

Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation

Authors:
- Jun Ren
- Shanshan Meng
- Bingdi Yan
- Jinyan Yu
- Jing Liu
View Affiliations

Affiliations: Department of Digestive System, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China, Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
Published online on: March 4, 2016 https://doi.org/10.3892/mmr.2016.4980
Pages: 3627-3638

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti‑inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A‑induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 µg/kg PD1 + Con A (30 mg/kg) group and 10 µg/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A‑induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro‑inflammatory cytokines, including tumor necrosis factor‑α, interferon‑γ and interleukin‑2, ‑1β and ‑6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll‑like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) signaling pathway and chemokine (C‑X3‑C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α and NF‑κB in Con A‑induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con A‑induced liver injury via inhibition of various inflammatory cytokines and, in part, by suppressing CD4+, CD8+ and NKT cell infiltration in the liver and the NF‑κB‑activated CX3CL1/CX3CR1 signaling pathway. The beneficial effect of PD1 may be associated with the inhibition of TLR4 expression and the downregulation of NF‑κB activation. In conclusion, PD1 appears to be a potential natural bioproduct, and provide a promising strategy, for the prevention of hepatic injury in patients with chronic or acute liver disease.

View Figures

View References

1	American Gastroenterological: AGA Institute guidelines on hepatitis B reactivation (HBVr): Clinical decision support tool. Gastroenterology. 148:2202015. View Article : Google Scholar
2	Lee H, Ainechi S, Dresser K and Kurian EM: Central portalization correlates with fibrosis but not with risk factors for nonalcoholic steatohepatitis in steatotic chronic hepatitis C. Int J Hepatol. 2014:3292972014.PubMed/NCBI
3	Gerlich WH: Prophylactic vaccination against hepatitis B: Achievements, challenges and perspectives. Med Microbiol Immunol. 204:39–55. 2014. View Article : Google Scholar : PubMed/NCBI
4	Hardtke-Wolenski M, Taubert R, Noyan F, Sievers M, Dywicki J, Schlue J, Falk CS, Ardesjö Lundgren B, Scott HS, Pich A, et al: Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens. Hepatology. 61:1295–1305. 2014. View Article : Google Scholar : PubMed/NCBI
5	Hart J, Ehlken H, Weiler-Normann C, Sebode M, Kreuels B, Pannicke N, Zenouzi R, Glaubke C, Lohse AW and Schramm C: Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis. J Hepatol. 62:642–646. 2015. View Article : Google Scholar
6	Lee JH, Won JH, Choi JM, Cha HH, Jang YJ, Park S, Kim HG, Kim HC and Kim DK: Protective effect of ellagic acid on concanavalin A-induced hepatitis via toll-like receptor and mitogen-activated protein kinase/nuclear factor κB signaling pathways. J Agric Food Chem. 62:10110–10117. 2014. View Article : Google Scholar : PubMed/NCBI
7	Tu CT, Han B, Yao QY, Zhang YA, Liu HC and Zhang SC: Curcumin attenuates concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression. Int Immunopharmacol. 12:151–157. 2012. View Article : Google Scholar
8	Chen YF, Wang SH, Chang SJ, Shiau AL, Her LS, Shieh GS, Chen CF, Chang CC, Su YC, Wu CL and Wu TS: Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis. Biochem Pharmacol. 91:217–230. 2014. View Article : Google Scholar : PubMed/NCBI
9	Crispe IN: Hepatic T cells and liver tolerance. Nat Rev Immunol. 3:51–62. 3002. View Article : Google Scholar
10	Panek CA, Ramos MV, Mejias MP, Abrey-Recalde MJ, Fernandez-Brando RJ, Gori MS, Salamone GV and Palermo MS: Differential expression of the fractalkine chemokine receptor (CXCR1) in human monocytes during differentiation. Cell Mol Immunol. 12:669–680. 2015. View Article : Google Scholar
11	Isse K, Harada K, Zen Y, Kamihira T, Shimoda S, Harada M and Nakanuma Y: Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. Hepatology. 41:506–516. 2005. View Article : Google Scholar : PubMed/NCBI
12	Ridderstad Wollberg A, Ericsson-Dahlstrand A, Juréus A, Ekerot P, Simon S, Nilsson M, Wiklund SJ, Berg AL, Ferm M, Sunnemark D and Johansson R: Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. Proc Natl Acad Sci USA. 111:5409–5414. 2014. View Article : Google Scholar : PubMed/NCBI
13	Pirvulescu MM, Gan AM, Stan D, Simion V, Calin M, Butoi E and Manduteanu I: Subendothelial resistin enhances monocyte transmigration in a co-culture of human endothelial and smooth muscle cells by mechanisms involving fractalkine, MCP-1 and activation of TLR4 and Gi/o proteins signaling. Int J Biochem Cell Biol. 50:29–37. 2014. View Article : Google Scholar : PubMed/NCBI
14	Bourd-Boittin K, Basset L, Bonnier D, L'helgoualc'h A, Samson M and Théret N: CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver. J Cell Mol Med. 13:1526–1535. 2009. View Article : Google Scholar : PubMed/NCBI
15	Efsen E, Grappone C, DeFranco RM, Milani S, Romanelli RG, Bonacchi A, Caliguri A, Failli P, Annunziato F, Pagliai G, et al: Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans. J Hepatol. 37:39–47. 2002. View Article : Google Scholar : PubMed/NCBI
16	Aoyama T, Inokuchi S, Brenner DA and Seki E: CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology. 52:1390–1400. 2010. View Article : Google Scholar : PubMed/NCBI
17	Xu ZZ, Liu XJ, Berta T, Park CK, Lü N, Serhan CN and Ji RR: Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann Neurol. 74:490–495. 2013. View Article : Google Scholar : PubMed/NCBI
18	Li X, Li C, Liang W, Bi Y, Chen M and Dong S: Protectin D1 promotes resolution of inflammation in a murine model of lipopolysaccharide-induced acute lung injury via enhancing neutrophil apoptosis. Chin Med J (Engl). 127:810–814. 2014.
19	Duffield JS, Hong S, Vaidya VS, Lu Y, Fredman G, Serhan CN and Bonventre JV: Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol. 177:5902–5911. 2006. View Article : Google Scholar : PubMed/NCBI
20	Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z, Tschopp J and Zhou R: Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 38:1154–1163. 2013. View Article : Google Scholar : PubMed/NCBI
21	Tsutsui H, Imamura M, Fujimoto J and Nakanishi K: The TLR4/TRIF-mediated activation of NLRP3 inflammasome underlies endotoxin-induced liver injury in mice. Gastroenterol Res Pract. 2010:6418652010. View Article : Google Scholar : PubMed/NCBI
22	Zhu J, Wang J, Sheng Y, Zou Y, Bo L, Wang F, Lou J, Fan X, Bao R, Wu Y, et al: Baicalin improves survival in a murine model of polymicrobial sepsis via suppressing inflammatory response and lymphocyte apoptosis. PLoS One. 7:e355232012. View Article : Google Scholar : PubMed/NCBI
23	Kato N, Matsumoto M, Kogawa M, Atkins GJ, Findlay DM, Fujikawa T, Oda H and Ogata M: Critical role of p38 MAPK for regeneration of the sciatic nerve following crush injury in vivo. J Neuroinflam. 10:Jan 3–2013. View Article : Google Scholar
24	DeSantis DA, Ko CW, Liu Y, Liu X, Hise AG, Nunez G and Croniger CM: Alcohol-induced liver injury is modulated by Nlrp3 and Nlrc4 inflammasomes in mice. Mediators Inflamm. 2013:7513742013. View Article : Google Scholar