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B Inhibitor Caspase Activating and Recruitment Domain 8 in Patients with Rheumatoid Arthritis Is Associated with Disease Severity1
* Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, Spain;
Servicio de Reumatologia, Hospital Universitario Marques de Valdecilla and Facultad de Medicina, Universidad de Cantabria, Santander, Spain;
Instituto de Formacion e Investigacion Marques de Valdecilla, Santander, Spain; and
Servicio de Reumatología, Hospital Universitario La Paz, Madrid, Spain
Caspase activating and recruitment domain 8 (CARD8) potently inhibits NF-
B signaling, which plays a key role in inflammation, and may contribute to avoid a pathologic activation of NF-B; however, the transcriptional mechanisms regulating CARD8 expression and the relevance of this protein in inflammatory diseases are poorly understood. We found a NF-B-binding element within the human CARD8 promoter that was required for transcriptional activity in response to TNF-
and the p65 subunit of NF-B. Moreover, TNF- and overexpression of p65 induced the formation of NF-B-CARD8 promoter complexes. Thus, CARD8 may control NF-B activation through a regulatory loop. To study the relevance of CARD8 in chronic inflammatory disorders, we functionally characterized a deleterious polymorphism (p.C10X) and studied its association with rheumatoid arthritis (RA). Transfection of cell lines with the allelic variants of CARD8 revealed that full-length (CARD8-L) but not truncated (CARD8-S) protein inhibits NF-B transcriptional activity, and abrogates the binding of NF-B to its consensus site. Furthermore, in contrast to the full-length protein, CARD8-S did not modify the expression of NF-B target genes (cIAP, A1), in response to TNF-. We analyzed the p.C10X polymorphism in 200 patients with RA, and found that homozygous carriers of the CARD8-S allele have higher disease activity score (p = 0.014), more extra-articular manifestations (p = 0.03), and a lower probability of clinical remission (p = 0.03) than the CARD8-L allele carriers. Overall, our findings provide molecular insight into the expression of CARD8 by NF-B, and suggest that a deleterious polymorphism of CARD8 may help predict the severity of RA.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants PI050169 and ISCIII-RETIC RD06/0020 from the Spanish Fondo de Investigacion Sanitaria, and API/06/02 from Fundacion Marques de Valdecilla-Instituto de Formacion e Investigacion Marques de Valdecilla.
2 Address correspondence and reprint requests to Dr. Jose L. Fernandez-Luna, Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Edificio Escuela Universitaria de Enfermeria, Avenuda Valdecilla s/n, 39008 Santander, Spain. E-mail address: fluna{at}humv.es
3 Abbreviations used in this paper: RA, rheumatoid arthritis; IKK, IB kinase; NLR, nucleotide-binding domain and leucine-rich repeat containing; DAS, disease activity score; SNP, single nucleotide polymorphism; CARD, caspase activating and recruitment domain.
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