title: Thioredoxin-1 ameliorates myosin-induced autoimmune myocarditis by suppressing chemokine expressions and leukocyte chemotaxis in mice.
abstract: BACKGROUND
  Cardiac myosin-induced myocarditis is an experimental autoimmune myocarditis (EAM) model used to investigate autoimmunological mechanisms in inflammatory heart diseases and resembles fulminant myocarditis in humans. We investigated the therapeutic role of thioredoxin-1 (TRX-1), a redox-regulatory protein with antioxidant and antiinflammatory effects, in murine EAM.
  
  
  RESULTS
  EAM was generated in 5-week-old male BALB/c mice by immunization with porcine cardiac myosin at days 0 and 7. Recombinant human TRX-1 (rhTRX-1), C32S/C35S mutant rhTRX-1, or saline was administered intraperitoneally every second day from day 0 to 20. In addition, rabbit anti-mouse TRX-1 serum or normal rabbit serum was administered intraperitoneally on days -1, 2, and 6. Animals were euthanized on day 21. Histological analysis of the heart showed that TRX-1 significantly reduced the severity of EAM, whereas mutant TRX-1 failed to have such an effect, and anti-TRX-1 antibody enhanced the disease markedly. Immunohistochemical analysis showed that TRX-1 significantly suppressed cardiac macrophage inflammatory protein (MIP)-1alpha, MIP-2, and 8-hydroxydeoxyguanosine expression and macrophage infiltration into the heart in EAM. Although serum levels of MIP-1alpha were not suppressed by TRX-1 until day 21, both an in vitro chemotaxis chamber assay and an in vivo air pouch model showed that TRX-1 significantly suppressed MIP-1alpha- or MIP-2-induced leukocyte chemotaxis. However, real-time reverse transcription-polymerase chain reaction showed that TRX-1 failed to decrease chemokine receptor expression increased in the bone marrow cells of EAM mice.
  
  
  CONCLUSIONS
  TRX-1 attenuates EAM by suppressing chemokine expressions and leukocyte chemotaxis in mice.
authors.affiliation: Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Wenrui
authors.initials: W
authors.lastname: Liu
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shioji
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanito
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Oka
authors.forename: M Kaimul
authors.initials: MK
authors.lastname: Ahsan
authors.forename: Aoi
authors.initials: A
authors.lastname: Son
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kishimoto
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D008214:Lymphocytes / Q000187:drug effects; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013879:Thioredoxins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; C491203:TXN protein, human; D013879:Thioredoxins; D009218:Myosins