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THU0371 Increased expression of inflammatory cytokines and chemokines in an autoinflammatory disorder, nakajo-nishimura syndrome
  1. K. Arima1,
  2. N. Kanazawa2,
  3. F. Furukawa2,
  4. H. Ida3,
  5. K. Yoshiura4
  1. 1Department of Medical Gene Technology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
  2. 2Department of Dermatology, Wakayama Medical University, Wakayama
  3. 3First Department of Internal Medicine, Kurume University, Kurume
  4. 4Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan


Background The ubiquitin-proteasome pathway is responsible for selective degradation of short-lived, misfolded and toxic proteins. It plays an important rule in transcriptional regulation.

Nakajo-Nishimura syndrome (NNS) (MIM 256040) is an autosomal recessive autoinflammatory disorder characterized by periodic fever, partial lipodystrophy, contracture of joints, skin rash and calcification of basal ganglia.

Homozygous mutation in the PSMB8 gene and decreased chymotrypsin-like activity indicated that dysfunction of the proteasome can result in the autoinflammatory condition.

Objectives To analyze the expression of inflammatory cytokines and chemokines in cells of proteasome impairment.

Methods Skin fibroblasts obtained from NNS patients (n=3) and healthy controls were cultured in the presence or absence of proteasome inhibitor. Gene expression of 84 inflammatory cytokines and receptors were analyzed by SYBR Green-based quantitative reverse transcription-PCR.

Serum samples were obtained from healthy controls (n=16), rheumatoid arthritis patients (n=5), and NNS patients (n=4). Concentrations of 48 different cytokines and chemokines were determined using a multiplex bead-based enzyme linked immunosorbent assay on a suspension array. Data were analyzed the Bio-Plex Manager 6.0 software.

Results 26 up-regulated genes and 3 down-regulated genes were identified in cultured cells under the condition of proteasome inhibition. Among these candidate genes CXCL-10 was significantly increased by the inhibition of proteasome (4.10-fold, p=0.008). This was compatible with the higher concentration of in sera of patient with NNS. IL-8 was significantly up-regulated both in cells treated with proteasome inhibitor (151.38 fold p<0.0001) and in cells obtained from patient with NNS (19.36 fold P<0.0001).

Conclusions These findings suggest that decrease of proteasome activity is associated with an increased expression of inflammatory cytokines. The ubiquitin-proteasome pathway would play an important rule against inflammation. This may provide a new insight into the pathogenesis of other persistent inflammatory diseases.

  1. Arima K, Kinoshita A, Mishima H et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci U S A. 2011;108:14914-9.

  2. Liu Y, Ramot Y, Torrelo A et al. Mutations in PSMB8 cause CANDLE syndrome with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. in press

Disclosure of Interest None Declared

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