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Differential influence of p38 mitogen activated protein kinase (MAPK) inhibition on acute phase protein synthesis in human hepatoma cell lines
  1. J Westra1,
  2. J Bijzet2,
  3. B Doornbos-van der Meer1,
  4. M H van Rijswijk1,
  5. P C Limburg1,2
  1. 1Department of Rheumatology, University Medical Centre Groningen, University of Groningen, The Netherlands
  2. 2Pathology and Laboratory Medicine, University Medical Centre Groningen, University of Groningen, The Netherlands
  1. Correspondence to:
    Dr J Westra
    Department of Rheumatology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands; j.westra{at}


Background: Inhibition of intracellular signal transduction is considered to be an interesting target for treatment in inflammation. p38 MAPK inhibitors, especially, have been developed and are now in phase II clinical trials for rheumatoid arthritis (RA).

Objective: To investigate the influence of p38 MAPK inhibition on acute phase protein (APP) production, which is dependent on both JAK/STAT and p38 MAPK pathways.

Methods: The effects of p38 MAPK inhibition on APP production and mRNA expression in four human hepatoma cell lines was investigated, after stimulation with interleukin (IL)6 and/or IL1β or tumour necrosis factor α.

Results: Two out of four cell lines produced C reactive protein (CRP), especially after combined IL6 and IL1β stimulation. CRP production was significantly inhibited by the p38 MAPK specific inhibitor RWJ 67657 at 1 μmol/l, which is pharmacologically relevant. Fibrinogen production was also inhibited at 1 μmol/l in all cell lines. Serum amyloid A (SAA) was produced in all four lines. In contrast with CRP, SAA production was not inhibited by RWJ 67657 at 1 μmol/l.

Conclusion: Production and mRNA expression of CRP and fibrinogen, but not SAA production and mRNA expression, were significantly inhibited by p38 MAPK specific inhibitor in hepatoma cell lines. For p38 MAPK inhibitor treatment in RA SAA might be a better marker of disease activity than CRP and fibrinogen, because SAA is not directly affected by p38 MAPK inhibition.

  • ANOVA, analysis of variance
  • APP, acute phase protein
  • CRP, C reactive protein
  • DMEM, Dulbecco’s modified Eagle’s medium
  • ELISA, enzyme linked immunosorbent assay
  • FCS, fetal calf serum
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • JAK, Janus kinase
  • IL, interleukin
  • MAPK, mitogen activated protein kinase
  • RA, rheumatoid arthritis
  • RT-PCR, reverse transcriptase-polymerase chain reaction
  • SAA, serum amyloid A
  • STAT, signal transducers and activators of transcription
  • TNF, tumour necrosis factor
  • C reactive protein
  • p38 MAPK
  • serum amyloid A
  • hepatoma cells
  • acute phase protein

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