NLRP2, an inhibitor of the NF-kappaB pathway, is transcriptionally activated by NF-kappaB and exhibits a nonfunctional allelic variant.
NLRP2 has been shown to inhibit the NF-kappaB signaling pathway, and thus may contribute to modulate the inflammatory response, where NF-kappaB plays a major role. In this study, we report that expression of NLRP2 is induced upon differentiation of CD34+ hemopoietic progenitors into granulocyte or monocyte/macrophages. We also found that NLRP2 was up-regulated following differentiation of mesenchymal stem cells toward adipocytes. Notably, stimulation of HEK293T cells with TNF-alpha or overexpression of the p65 subunit of NF-kappaB resulted in up-regulation of NLRP2 and the formation of NF-kappaB-NLRP2 promoter complexes. Moreover, ectopic expression of p65 but not of other transcriptional regulators induced transactivation of the NLRP2 promoter. Thus, NLRP2 may control NF-kappaB activation through a regulatory loop. Nucleotide changes within the NACHT domain of other NLRP proteins have been associated with hereditary fever syndromes and chronic inflammatory diseases. We identified five single nucleotide polymorphisms present in the NACHT domain of NLRP2 by sequencing genomic DNA from 319 healthy controls. The frequencies of the rare alleles varied between 0.2 and 10%. Of note, one of these variants, I352S was unable to block the transcriptional activity of NF-kappaB and the formation of NF-kappaB-DNA-binding complexes following stimulation with TNF-alpha. Overall, our findings provide molecular insight into the expression of NLRP2 by NF-kappaB and suggest that a polymorphism within the NACHT domain of NLRP2 may contribute to the amplification of inflammatory responses due to a reduction of inhibitory signals on the NF-kappaB pathway.
Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, Spain.
Ana
A
Fontalba
Olga
O
Gutierrez
Jose L
JL
Fernandez-Luna
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005787:Gene Frequency; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020641:Polymorphism, Single Nucleotide; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; C495732:NLRP2 protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha