title: Mycobacterium tuberculosis induces interleukin-32 production through a caspase- 1/IL-18/interferon-gamma-dependent mechanism.
abstract: BACKGROUND
  Interleukin (IL)-32 is a newly described proinflammatory cytokine that seems likely to play a role in inflammation and host defense. Little is known about the regulation of IL-32 production by primary cells of the immune system.
  
  
  RESULTS
  In the present study, freshly obtained human peripheral blood mononuclear cells were stimulated with different Toll-like receptor (TLR) agonists, and gene expression and synthesis of IL-32 was determined. We demonstrate that the TLR4 agonist lipopolysaccharide induces moderate (4-fold) production of IL-32, whereas agonists of TLR2, TLR3, TLR5, or TLR9, each of which strongly induced tumor necrosis factor alpha and IL-6, did not stimulate IL-32 production. However, the greatest amount of IL-32 was induced by the mycobacteria Mycobacterium tuberculosis and M. bovis BCG (20-fold over unstimulated cells). IL-32-induced synthesis by either lipopolysaccharide or mycobacteria remains entirely cell-associated in monocytes; moreover, steady-state mRNA levels are present in unstimulated monocytes without translation into IL-32 protein, similar to other cytokines lacking a signal peptide. IL-32 production induced by M. tuberculosis is dependent on endogenous interferon-gamma (IFNgamma); endogenous IFNgamma is, in turn, dependent on M. tuberculosis-induced IL-18 via caspase-1.
  
  
  CONCLUSIONS
  In conclusion, IL-32 is a cell-associated proinflammatory cytokine, which is specifically stimulated by mycobacteria through a caspase-1- and IL-18-dependent production of IFNgamma.
authors.affiliation: Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA. M.Netea@aig.umcn.nl
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Maorong
authors.initials: M
authors.lastname: Wang
authors.forename: Dennis
authors.initials: D
authors.lastname: Langenberg
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Yoon
authors.forename: Tom
authors.initials: T
authors.lastname: Ottenhoff
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D020170:Caspase 1 / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D020382:Interleukin-18 / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C496971:IL32 protein, human; D020382:Interleukin-18; D007378:Interleukins; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D012333:RNA, Messenger; D007371:Interferon-gamma; D020170:Caspase 1