title: 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.
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.
authors.affiliation: Department of Digestive System, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Meng
authors.affiliation: Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China.
authors.forename: Bingdi
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D054428:Chemokine CX3CL1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000032:analysis; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D058847:Inflammasomes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D000637:Transaminases / Q000097:blood
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D019707:Receptors, Chemokine; D051197:Toll-Like Receptor 4; C487679:protectin D1; D003208:Concanavalin A; D004281:Docosahexaenoic Acids; D000637:Transaminases