title: Towards a role of interleukin-32 in atherosclerosis.
abstract: BACKGROUND
  IL-32 has been previously shown to promote inflammation in rheumatoid arthritis patients and to contribute to IL-1β-induced ICAM-1 as well as other proinflammatory cytokines synthesis in human umbilical endothelial cells (HUVECs). Given the high rate of atherosclerosis in RA, these observations suggest that IL-32 may be involved in the inflammatory pathways of atherosclerosis.
  
  
  METHODS
  mRNA and protein levels of IL-32 were determined in human atherosclerotic arterial vessel wall tissue by quantitative real-time PCR and immunohistochemistry. HUVEC and M1/M2 macrophages were stimulated with proinflammatory cytokines and TLR ligands to assess IL-32 mRNA induction. Human THP1 macrophages were transduced with AdIL-32γ, to investigate induction of several proatherosclerotic mediators. Finally, aortas from IL-32γ transgenic mice were studied and compared with aortas from age-matched wild-type mice.
  
  
  RESULTS
  IL-32 expression was detectable in human atherosclerotic arterial vessel wall, with the expression of IL-32β and IL-32γ mRNA significantly enhanced. TLR3-ligand Poly I:C in combination with IFNγ were the most potent inducers of IL-32 mRNA expression in both HUVEC and M1/M2 macrophages. Adenoviral overexpression of IL-32γ in human THP1 macrophages resulted in increased production of CCL2, sVCAM-1, MMP1, MMP9, and MMP13. The IL-32γ transgenic mice chow a normal fat diet exhibited vascular abnormalities resembling atherosclerosis.
  
  
  CONCLUSIONS
  IL-32 acts as a proinflammatory factor and may be implicated in the inflammatory cascade contributing to atherosclerosis. By promoting the synthesis of matrix metalloproteinases, it may further contribute to plaque instability. Further studies are warranted to investigate whether IL-32 may serve as a potential therapeutic target in fighting atherosclerosis.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands; Department of Rheumatology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation and Immunity, 6500 HB Nijmegen, The Netherlands. Electronic address: s.heinhuis@aig.umcn.nl.
authors.forename: Bas
authors.initials: B
authors.lastname: Heinhuis
authors.forename: Calin D
authors.initials: CD
authors.lastname: Popa
authors.forename: Berry L J H
authors.initials: BL
authors.lastname: van Tits
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Zeeuwen
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: J Adam
authors.initials: JA
authors.lastname: van der Vliet
authors.forename: Anton F H
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C496971:IL32 protein, human; D007378:Interleukins; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D007371:Interferon-gamma; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Cytokines; Interleukin-32; Matrix metalloproteinases; Plaque instability; TLR-ligands