TY - JOUR
T1 - Mycobacterium tuberculosis induces interleukin-32 production through a caspase-1/IL-18/interferon-γ-dependent mechanism
AU - Netea, Mihai G.
AU - Azam, Tania
AU - Lewis, Eli C.
AU - Joosten, Leo A.B.
AU - Wang, Maorong
AU - Langenberg, Dennis
AU - Meng, Xianzhong
AU - Chan, Edward D.
AU - Yoon, Do Young
AU - Ottenhoff, Tom
AU - Kim, Soo Hyun
AU - Dinarello, Charles A.
PY - 2006/9/12
Y1 - 2006/9/12
N2 - 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. Methods and Findings: 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 a 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-γ (IFNγ); endogenous IFNγ 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 IFNγ.
AB - 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. Methods and Findings: 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 a 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-γ (IFNγ); endogenous IFNγ 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 IFNγ.
UR - http://www.scopus.com/inward/record.url?scp=33748369134&partnerID=8YFLogxK
U2 - 10.1371/journal.pmed.0030277
DO - 10.1371/journal.pmed.0030277
M3 - Article
AN - SCOPUS:33748369134
SN - 1549-1277
VL - 3
SP - 1310
EP - 1319
JO - PLoS Medicine
JF - PLoS Medicine
IS - 8
ER -