HLA-B27 modulates nuclear factor kappaB activation in human monocytic cells exposed to lipopolysaccharide

Arthritis Rheum. 2002 Aug;46(8):2172-80. doi: 10.1002/art.10557.

Abstract

Objective: To study whether HLA-B27 modifies some key factors controlling inflammatory responses on lipopolysaccharide (LPS) stimulation in human monocytic cells.

Methods: U937 human monocytic cells were stably transfected with either HLA-B27 genomic DNA, HLA-B27 complementary DNA, HLA-A2 genomic DNA, or with the resistant vector pSV2neo (mock) alone. The cells were stimulated with LPS. Electrophoretic mobility shift assay was performed to determine nuclear factor kappaB (NF-kappaB) and heat-shock factor 1 activities, Western blotting was performed to detect the expressions of inhibitory kappaBalpha (IkappaBalpha) and heat-shock proteins (HSPs), and enzyme-linked immunosorbent assay was performed to measure tumor necrosis factor alpha (TNFalpha) secretion.

Results: The expression of HLA-B27 modulated the response to LPS in U937 human monocytic cells. Stimulation with LPS led to faster degradation of IkappaBalpha regulatory proteins, accompanied by faster and prolonged activation of NF-kappaB in HLA-B27-expressing cells compared with HLA-A2 and mock transfectants. The secretion of TNFalpha upon LPS stimulation correlated well with the activation of NF-kappaB. No activation of the heat-shock response was observed.

Conclusion: Our data indicate that HLA-B27 has effects on host responses to LPS that are unrelated to antigen presentation. Two crucial events in the development of arthritis, the activation of NF-kappaB and the secretion of TNFalpha, were found to be enhanced in HLA-B27-expressing cells upon LPS stimulation. Because LPS is known to be present in the inflamed joints of patients with reactive arthritis (ReA), the enhanced inflammatory response of HLA-B27-positive cells upon LPS stimulation offers an attractive explanation for the role of HLA-B27 in the development of ReA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / metabolism
  • HLA-B7 Antigen / genetics
  • HLA-B7 Antigen / immunology*
  • Heat Shock Transcription Factors
  • Humans
  • Lipopolysaccharides / pharmacology
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism*
  • NF-kappa B / biosynthesis*
  • Salmonella enteritidis / immunology
  • Transcription Factors
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism*
  • U937 Cells

Substances

  • DNA-Binding Proteins
  • HLA-B7 Antigen
  • Heat Shock Transcription Factors
  • Lipopolysaccharides
  • NF-kappa B
  • Transcription Factors
  • Tumor Necrosis Factor-alpha