Transcriptional and inflammasome-mediated pathways for the induction of IL-1beta production by Mycobacterium tuberculosis.
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-1beta, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1beta 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-1beta induction. Recognition of M. tuberculosis by TLR and NOD2 leads to transcription of proIL-1beta through mechanisms involving ERK, p38 and Rip2, but not JNK. Interestingly, although caspase-1 is necessary for the processing of proIL-1beta, 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-1beta is dependent on the activation of P2X7-induced pathways by endogenously released ATP. In conclusion, we have dissected the molecular mechanisms responsible for IL-1beta production by M. tuberculosis, and that may contribute to a deeper knowledge of the mechanisms of cell activation by M. tuberculosis.
Kleinnijenhuis
Johanneke
J
Department of Medicine, Radboud University Nijmegen Medical Center, The Netherlands. m.netea@aig.umcn.nl
Joosten
Leo A B
LA
van de Veerdonk
Frank L
FL
Savage
Nigel
N
van Crevel
Reinout
R
Kullberg
Bart Jan
BJ
van der Ven
Andre
A
Ottenhoff
Tom H M
TH
Dinarello
Charles A
CA
van der Meer
Jos W M
JW
Netea
Mihai G
MG
D000818:Animals; D015153:Blotting, Western; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495369:Tlr6 protein, mouse; C495370:Tlr9 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051217:Toll-Like Receptor 9; D020170:Caspase 1