PMID- 28028363 OWN - NLM STAT- MEDLINE DCOM- 20170609 LR - 20181113 IS - 2219-2840 (Electronic) IS - 1007-9327 (Print) IS - 1007-9327 (Linking) VI - 22 IP - 46 DP - 2016 Dec 14 TI - C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38-MAPK activation in acute liver failure. PG - 10148-10157 LID - 10.3748/wjg.v22.i46.10148 [doi] AB - AIM: To investigate the role of the complement 5a (C5a)/C5a receptor (C5aR) pathway in the pathogenesis of acute liver failure (ALF) in a mouse model. METHODS: BALB/c mice were randomly assigned to different groups, and intraperitoneal injections of lipopolysaccharide (LPS)/D-galactosamine (D-GalN) (600 mg/kg and 10 mug/kg) were used to induce ALF. The Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase (ALT) levels, at different time points within a 1-wk period, were detected with a biochemistry analyzer. Pathological examination of liver tissue was performed 36 h after ALF induction. Serum complement 5 (C5), C5a, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, high-mobility group protein B1 (HMGB1) and sphingosine-1-phosphate levels were detected by enzyme-linked immunosorbant assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of C5aR, sphingosine kinase 1 (SphK1), p38-MAPK and p-p38-MAPK in liver tissue, peripheral blood mononuclear cells (PBMCs) and peritoneal exudative macrophages (PEMs) of mice or RAW 264.7 cells was analyzed by western blotting. C5aR mRNA levels were detected by quantitative real-time PCR. RESULTS: Activation of C5 and up-regulation of C5aR were observed in liver tissue and PBMCs of mice with ALF. Blockade of C5aR with a C5aR antagonist (C5aRa C5aRa) significantly reduced the levels of serum ALT, inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and HMGB1, as well as the liver tissue damage, but increased the survival rates (P < 0.01 for all). Blockade of C5aR decreased SphK1 expression in both liver tissue and PBMCs significantly at 0.5 h after ALF induction. C5aRa pretreatment significantly down-regulated the phosphorylation of p38-MAPK in liver tissues of ALF mice and C5a stimulated PEMs or RAW 264.7 cells. Moreover, inhibition of p38-MAPK activity with SB203580 reduced SphK1 protein production significantly in PEMs after C5a stimulation. CONCLUSION: The C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38 MAPK activation in ALF in mice, which provides a potential immunotherapeutic strategy for ALF in patients. FAU - Lei, Yan-Chang AU - Lei YC AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. FAU - Lu, Chun-Lei AU - Lu CL AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. FAU - Chen, Ling AU - Chen L AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. FAU - Ge, Ke AU - Ge K AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. FAU - Yang, Ling-Ling AU - Yang LL AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. FAU - Li, Wen AU - Li W AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. FAU - Wu, Yuan-Hua AU - Wu YH AD - Yan-Chang Lei, Ling Chen, Ke Ge, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China. LA - eng PT - Journal Article PL - United States TA - World J Gastroenterol JT - World journal of gastroenterology JID - 100883448 RN - 0 (HMGB1 Protein) RN - 0 (HMGB1 protein, mouse) RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (Lysophospholipids) RN - 0 (RNA, Messenger) RN - 0 (Receptor, Anaphylatoxin C5a) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (interleukin-6, mouse) RN - 26993-30-6 (sphingosine 1-phosphate) RN - 7535-00-4 (Galactosamine) RN - 80295-54-1 (Complement C5a) RN - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.- (sphingosine kinase) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Animals MH - Blotting, Western MH - Complement C5a/*metabolism MH - Disease Models, Animal MH - Enzyme-Linked Immunosorbent Assay MH - Galactosamine/toxicity MH - HMGB1 Protein/metabolism MH - Interleukin-1beta/metabolism MH - Interleukin-6/metabolism MH - Kaplan-Meier Estimate MH - Leukocytes, Mononuclear/metabolism MH - Lipopolysaccharides/toxicity MH - Liver/*metabolism/pathology MH - Liver Failure, Acute/chemically induced/*metabolism/pathology MH - Lysophospholipids/metabolism MH - Macrophages, Peritoneal/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - RNA, Messenger/*metabolism MH - Random Allocation MH - Real-Time Polymerase Chain Reaction MH - Receptor, Anaphylatoxin C5a/genetics/*metabolism MH - Signal Transduction MH - Sphingosine/analogs & derivatives/metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - p38 Mitogen-Activated Protein Kinases/*metabolism PMC - PMC5155174 OTO - NOTNLM OT - Acute liver failure OT - C5a/C5aR OT - Sphingosine kinase 1 OT - p38-MAPK COIS- Conflict-of-interest statement: We declare that there are no conflicts of interest to disclose. EDAT- 2016/12/29 06:00 MHDA- 2017/06/10 06:00 PMCR- 2016/12/14 CRDT- 2016/12/29 06:00 PHST- 2016/08/02 00:00 [received] PHST- 2016/09/08 00:00 [revised] PHST- 2016/10/10 00:00 [accepted] PHST- 2016/12/29 06:00 [entrez] PHST- 2016/12/29 06:00 [pubmed] PHST- 2017/06/10 06:00 [medline] PHST- 2016/12/14 00:00 [pmc-release] AID - 10.3748/wjg.v22.i46.10148 [doi] PST - ppublish SO - World J Gastroenterol. 2016 Dec 14;22(46):10148-10157. doi: 10.3748/wjg.v22.i46.10148.