title: Leptin and Neutrophil-Activating Peptide 2 Promote Mesenchymal Stem Cell Senescence Through Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway in Patients With Systemic Lupus Erythematosus.
abstract: OBJECTIVE
  Mesenchymal stem cells (MSCs) derived from patients with systemic lupus erythematosus (SLE) exhibit enhanced senescence. Cellular senescence has been reported to be induced by several inflammatory cytokines, including interferon-α (IFNα) and IFNγ, that are involved in the pathogenesis of SLE. We undertook this study to investigate whether the inflammatory environment in SLE could affect MSC senescence.
  
  
  METHODS
  Cellular senescence was measured by staining of senescence-associated β-galactosidase and by expression of the cell cycle inhibitors p53 and p21. Eighty cytokines and chemokines in serum from healthy controls and patients with SLE were identified by cytokine antibody array.
  
  
  RESULTS
  SLE serum promoted senescence of MSCs, which was reversed by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling inhibitor LY294002 but not by the JAK/STAT inhibitor AG490 and not by the MEK/ERK inhibitor PD98059. Cytokine antibody array analysis revealed that leptin and neutrophil-activating peptide 2 (NAP-2) were the 2 factors most significantly elevated in SLE serum compared with normal serum. Blockade of leptin or NAP-2 in MSC cultures abolished SLE serum-induced senescence, while direct addition of these 2 factors could promote senescence in cultures of normal MSCs. Inhibition of PI3K/Akt signaling with LY294002 reduced leptin- and NAP-2-induced senescence in MSCs.
  
  
  CONCLUSIONS
  Taken together, our data show that leptin and NAP-2 act synergistically to promote MSC senescence through enhancement of the PI3K/Akt signaling pathway in SLE patients.
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Shi
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Feng
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chen
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Linyu
authors.initials: L
authors.lastname: Geng
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: WanJun
authors.initials: W
authors.lastname: Chen
authors.affiliation: Nanjing University, Nanjing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Nanjing University and The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D016922:Cellular Senescence / Q000276:immunology*; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D020738:Leptin / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D009025:Morpholines / Q000494:pharmacology; D010455:Peptides / Q000276:immunology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050791:STAT Transcription Factors; D015398:Signal Transduction / Q000276:immunology; D020032:Tyrphostins / Q000494:pharmacology; D055815:Young Adult
chemical_list: D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020738:Leptin; D009025:Morpholines; D010455:Peptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C009862:connective tissue-activating peptide; D058539:Phosphatidylinositol 3-Kinase; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one