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Functional interactions between PI3-kinase and NF-κB signaling pathways promote joint destruction in rheumatoid arthritis
  1. L M Hartkamp,
  2. A M Grabiec,
  3. J Ludikhuize,
  4. I E van Es,
  5. M E Sanders,
  6. P P Tak,
  7. K A Reedquist
  1. Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands


Background and objectives Rheumatoid arthritis (RA) synovium is characterised by hyperplasia of fibroblast-like synoviocytes (FLS), which display properties of transformed cells. Regulation of proto-oncogenic phosphatidylinositol 3-kinase (PI3-K) signaling by components of the NF-κB signal transduction pathway has emerged as a candidate molecular mechanism linking inflammation to cancer. Conversely, activation of PI3-K pathways in genetically engineered mice, via reducing expression of PTEN or FoxO transcription factors or transgenically expressing constitutively active PKB, can drive NF-κB-mediated autoimmunity. Here we examined potential functional relationships between PI3-K and NF-κB signaling in RA FLS and synovial tissue.

Materials and methods Expression and/or phosphorylation of IKKβ, IkBα, PTEN, a negative regulator of PI3-kinase, PKB and FoxO1, downstream targets of PI3-kinase, was detected by immunohistochemistry combined with digital image analysis in synovial tissue from 15 disease-modifying antirheumatic drug (DMARD)-naïve RA patients. Biopsies were obtained at baseline, and x-rays made of hands and feet at baseline and at 2 years follow-up. At 2 years, patients were classified as having non-erosive or erosive disease (Sharp van der Heijde score > 2). Effects of the pan-PI3-K inhibitor LY294002 and inhibitors specific for α/β, γ and λ isoforms of PI3-K on RA FLS IL-1β-induced IkBα phosphorylation and NF-κB p65 activation were assessed by immunoblotting and ELISA, respectively.

Results In vivo we observed a strong correlation between expression of IKKβ and phosphorylation of IκBα (r = 0.83, p < 0.005) in RA synovial tissue, but IKKβ did not downregulate PTEN or FoxO protein expression, as predicted by tumour models. Instead, we observed a strong positive correlation between PKB activation, phosphorylation of FoxO1 (r = 0.90, p < 0.0001) and activation of NF-κB signalling (r = 0.56, p < 0.05), and NF-κB signaling was elevated in patients with accelerated progressive disease (p < 0.05). In vitro, sustained phosphorylation of IkBα and activation of NF-κB in RA FLS by IL-1β stimulation required PI3-K activity.

Conclusions Our studies provide evidence that PI3-K signaling pathways may contribute to joint destruction in RA through enhancement of NF-κB-dependent gene transcription and that PI3-kinase inhibitors may be effective in preventing disease progression.

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