Mycobacterium tuberculosis induces interleukin-32 production through a caspase- 1/IL-18/interferon-gamma-dependent mechanism.
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.
Netea
Mihai G
MG
Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA. M.Netea@aig.umcn.nl
Azam
Tania
T
Lewis
Eli C
EC
Joosten
Leo A B
LA
Wang
Maorong
M
Langenberg
Dennis
D
Meng
Xianzhong
X
Chan
Edward D
ED
Yoon
Do-Young
DY
Ottenhoff
Tom
T
Kim
Soo-Hyun
SH
Dinarello
Charles A
CA
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
C496971:IL32 protein, human; D020382:Interleukin-18; D007378:Interleukins; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D012333:RNA, Messenger; D007371:Interferon-gamma; D020170:Caspase 1