Caspase-12 and the inflammatory response to Yersinia pestis.
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.


RESULTS
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.
Ferwerda
Bart
B
Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. E.ferwerda@aig.umcn.nl
McCall
Matthew B B
MB
de Vries
Maaike C
MC
Hopman
Joost
J
Maiga
Boubacar
B
Dolo
Amagana
A
Doumbo
Ogobara
O
Daou
Modibo
M
de Jong
Dirk
D
Joosten
Leo A B
LA
Tissingh
Rudi A
RA
Reubsaet
Frans A G
FA
Sauerwein
Robert
R
van der Meer
Jos W M
JW
van der Ven
André J A M
AJ
Netea
Mihai G
MG
D053454:Caspase 12 / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008302:Mali; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D015009:Yersinia Infections / Q000378:metabolism*; D015010:Yersinia pestis / Q000472:pathogenicity*
D016207:Cytokines; D053583:Interleukin-1beta; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053454:Caspase 12