Transcriptional and inflammasome-mediated pathways for the induction of IL-1β production by Mycobacterium tuberculosis

Abstract

Proinflammatory cytokines of the IL-1 family play an important role for the anti-mycobacterial host defense mechanisms. In the present study we have deciphered the pathways leading from recognition of Mycobacterium tuberculosis to the production and release of IL-1β, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1β production is induced by M. tuberculosis through pathways involving TLR2/TLR6 and NOD2 receptors. In contrast, TLR4, TLR9 and TLR1 receptors are not involved in IL-1β induction. Recognition of M. tuberculosis by TLR and NOD2 leads to transcription of proIL-1β through mechanisms involving ERK, p38 and Rip2, but not JNK. Interestingly, although caspase-1 is necessary for the processing of proIL-1β, activation of caspase-1 is not dependent on the stimulation of cells by M. tuberculosis. Monocytes expressed constitutively active caspase-1. The secretion of IL-1β is dependent on the activation of P2X7-induced pathways by endogenously released ATP. In conclusion, we have dissected the molecular mechanisms responsible for IL-1β production by M. tuberculosis, and that may contribute to a deeper knowledge of the mechanisms of cell activation by M. tuberculosis. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.