title: Artesunate inhibits type I interferon-induced production of macrophage migration inhibitory factor in patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  Macrophage migration inhibitory factor (MIF) is a key regulator of both atherosclerosis and systemic lupus erythematosus (SLE), yet factors leading to its overproduction remain unclear. To explore regulation of MIF in SLE, we studied effects and potential mechanisms of type I interferon (IFN) and artesunate (ART), an antimalarial agent extracted from Chinese herbs, on levels of MIF.
  
  
  METHODS
  Serum and peripheral blood cells from SLE patients and healthy controls were measured for MIF levels by ELISA and type I IFN-inducible gene expressions by real-time PCR, respectively, and assessed for associations by Spearman correlation. ART was added to human umbilical vein endothelial cell (HUVEC) cultures with or without prior IFNα-1b stimulation and to SLE peripheral blood mononuclear cell (PBMC) cultures. Protein levels of STATs and phosphorylated (p-) STATs in HUVECs were determined by Western blotting.
  
  
  RESULTS
  Serum MIF levels were elevated in SLE patients and positively associated with disease activity (r = 0.86, p < 0.0001), accumulated damage (r = 0.34, p < 0.05), and IFN scores in SLE PBMCs (r = 0.74, p = 0.0002). The addition of IFNα-1b promoted MIF production in a time- and dose-dependent manner in HUVEC cultures. ART could inhibit expressions of IFN-inducible genes (LY6E and ISG15) in both HUVEC and SLE PBMC cultures, and suppress MIF production and over-expression of p-STAT1, but not p-STAT3 or STAT5, induced by IFNα-1b stimulation. IFNγ-induced expression of p-STAT1 in HUVECs was not inhibited by ART.
  
  
  CONCLUSIONS
  MIF could be regulated by type I IFN in SLE patients. ART counteracts the effect of IFNα to inhibit MIF production by blocking STAT1 phosphorylation and thus may have therapeutic potential for SLE-associated atherosclerosis.
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China fengxuebing@hotmail.com lingyunsun@nju.edu.cn.
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: F
authors.initials: F
authors.lastname: Gu
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Sun
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D000077332:Artesunate; D015153:Blotting, Western; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000008:administration & dosage / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000503:physiopathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D007370:Interferon Type I; D016898:Interferon-alpha; D008263:Macrophage Migration-Inhibitory Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000077332:Artesunate; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: Systemic lupus erythematosus; artesunate; interferon; macrophage migration inhibitory factor; signal transducer and activator of transcription 1