title: Hydrogen sulfide inhibits abnormal proliferation of lymphocytes via AKT/GSK3β signal pathway in systemic lupus erythematosus patients.
abstract: OBJECTIVE
  The abnormal activation of the AKT/GSK3β signal pathway in lymphocytes from systemic lupus erythematosus (SLE) patients plays an important role in the pathogenesis of the disease. Recently Hydrogen sulfide (H2S) has been recognized as a crucial gaseous signaling molecule, involved in regulation of cell proliferation. However, the role of H2S in regulating the abnormal activation of lymphocytes from SLE patients has not been established. This study was conducted to investigate the effect of H2S on lymphocytes and to explore the mechanisms involved.
  
  
  METHODS
  The lymphocytes were isolated from SLE patients with or without renal disease and healthy controls. The cells were treated as indicated in each experiment. Cell viability was analyzed by CCK-8. Cell cycle distribution was determined by flow cytometry. Western blot was used to detect the expression of phosphorylated AKT (ser473), GSK3β (ser9) and CDK2, p27(Kip1) and p21(WAF1/CIP1).
  
  
  RESULTS
  Our findings showed that proliferation of lymphocytes was stimulated following treatment with NaHS (a H2S donor) at low NaHS concentrations (<1mM) but inhibited at high NaHS concentrations (>2mM). Similar results were observed using GYY4137, which is a slow-releasing H2S donor. Pretreatment of lymphocytes from SLE patients with NaHS at high concentrations prior to exposure to phytohemagglutinin (PHA) significantly attenuated proliferation, evidenced by decrease in cell viability and S phase distribution of cell cycle. Pretreatment with NaHS decreased PHA-induced expression of CDK2, phosphorylation levels of AKT (ser473) and GSK3β (ser9) and increased the expression of p27(Kip1) and p21(WAF1/CIP1). Moreover, pretreatment with NaHS blunted the stimulation of SLE lymphocyte proliferation by GSK3β inhibitor lithium chloride.
  
  
  CONCLUSIONS
  These results demonstrate that H2S inhibits the abnormal activation of lymphocytes from SLE patients throuqh the AKT/GSK3β signal pathway.
authors.affiliation: Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; 107 Yanjian West Road, Guangzhou, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Han
authors.forename: Fanqin
authors.initials: F
authors.lastname: Zeng
authors.forename: Guozhen
authors.initials: G
authors.lastname: Tan
authors.forename: Chuntao
authors.initials: C
authors.lastname: Yang
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Tang
authors.forename: Yijin
authors.initials: Y
authors.lastname: Luo
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Feng
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D010835:Phytohemagglutinins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D006862:Hydrogen Sulfide