期刊
JOURNAL OF IMMUNOLOGY
卷 195, 期 11, 页码 5415-5420出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1501532
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资金
- Instituto de Salud Carlos III
- Spanish Ministry of Science and Innovation [PI11/02012]
- Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0022]
- Federacion Espanola de Reumatologia [FER13/13]
- Instituto de Investigacion Valdecilla Grant [APG-03]
- programa Ramon y Cajal, Ministerio de Economia y Competitividad, Spain
Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-kappa B may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-kappa B pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-kB target genes (TRAIL, TNF-alpha, cIAP-1, IL8) and blocks activation of a NF-kappa B-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-kappa B inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-kappa B and the secretion of TNF-alpha in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-kappa B activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.
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