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.