title: Caspase-12 and the inflammatory response to Yersinia pestis.
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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. E.ferwerda@aig.umcn.nl
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.forename: Matthew B B
authors.initials: MB
authors.lastname: McCall
authors.forename: Maaike C
authors.initials: MC
authors.lastname: de Vries
authors.forename: Joost
authors.initials: J
authors.lastname: Hopman
authors.forename: Boubacar
authors.initials: B
authors.lastname: Maiga
authors.forename: Amagana
authors.initials: A
authors.lastname: Dolo
authors.forename: Ogobara
authors.initials: O
authors.lastname: Doumbo
authors.forename: Modibo
authors.initials: M
authors.lastname: Daou
authors.forename: Dirk
authors.initials: D
authors.lastname: de Jong
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Rudi A
authors.initials: RA
authors.lastname: Tissingh
authors.forename: Frans A G
authors.initials: FA
authors.lastname: Reubsaet
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: 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*
chemical_list: 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