Differential influence of p38 mitogen activated protein kinase (MAPK) inhibition on acute phase protein synthesis in human hepatoma cell lines.
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 IL1beta or tumour necrosis factor alpha.


RESULTS
Two out of four cell lines produced C reactive protein (CRP), especially after combined IL6 and IL1beta stimulation. CRP production was significantly inhibited by the p38 MAPK specific inhibitor RWJ 67657 at 1 micromol/l, which is pharmacologically relevant. Fibrinogen production was also inhibited at 1 micromol/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 micromol/l.


CONCLUSIONS
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.
Westra
J
J
Department of Rheumatology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. j.westra@med.umcg.nl
Bijzet
J
J
Doornbos-van der Meer
B
B
van Rijswijk
M H
MH
Limburg
P C
PC
D000209:Acute-Phase Proteins / Q000096:biosynthesis*; D000704:Analysis of Variance; D015153:Blotting, Western / Q000379:methods; D002097:C-Reactive Protein / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D003176:Complement C3 / Q000096:biosynthesis; D005340:Fibrinogen / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007114:Immunization; D007375:Interleukin-1 / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D000685:Serum Amyloid A Protein / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000209:Acute-Phase Proteins; D003176:Complement C3; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D012333:RNA, Messenger; C400277:RWJ 67657; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases