Mycobacterium tuberculosis induces interleukin-32 production through a caspase-1/IL-18/interferon-γ-dependent mechanism

Mihai G. Netea, Tania Azam, Eli C. Lewis, Leo A.B. Joosten, Maorong Wang, Dennis Langenberg, Xianzhong Meng, Edward D. Chan, Do Young Yoon, Tom Ottenhoff, Soo Hyun Kim, Charles A. Dinarello

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

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. 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.

Original languageEnglish
Pages (from-to)1310-1319
Number of pages10
JournalPLoS Medicine
Volume3
Issue number8
DOIs
StatePublished - 12 Sep 2006
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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