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Caspase-12 and the Inflammatory Response to Yersinia pestis
Authors:Bart Ferwerda  Matthew B B McCall  Maaike C de Vries  Joost Hopman  Boubacar Maiga  Amagana Dolo  Ogobara Doumbo  Modibo Daou  Dirk de Jong  Leo A B Joosten  Rudi A Tissingh  Frans A G Reubsaet  Robert Sauerwein  Jos W M van der Meer  André J A M van der Ven  Mihai G Netea
Abstract:

Background

Caspase-12 functions as an antiinflammatory enzyme inhibiting caspase-1 and the NOD2/RIP2 pathways. Due to increased susceptibility to sepsis in individuals with functional caspase-12, an early-stop mutation leading to the loss of caspase-12 has replaced the ancient genotype in Eurasia and a significant proportion of individuals from African populations. In African-Americans, it has been shown that caspase-12 inhibits the pro-inflammatory cytokine production.

Methodology/Principal Findings

We assessed whether similar mechanisms are present in African individuals, and whether evolutionary pressures due to plague may have led to the present caspase-12 genotype population frequencies. No difference in cytokine induction through the caspase-1 and/or NOD2/RIP2 pathways was observed in two independent African populations, among individuals with either an intact or absent caspase-12. In addition, stimulations with Yersinia pestis and two other species of Yersinia were preformed to investigate whether caspase-12 modulates the inflammatory reaction induced by Yersinia. We found that caspase-12 did not modulate cytokine production induced by Yersinia spp.

Conclusions

Our experiments demonstrate for the first time the involvement of the NOD2/RIP2 pathway for recognition of Yersinia. However, caspase-12 does not modulate innate host defense against Y. pestis and alternative explanations for the geographical distribution of caspase-12 should be sought.
Keywords:
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