Differential pharmacological behaviour of p38 inhibitors in regulating the LPS-induced TNF-α production in human and rat whole blood in vitro.
p38 inhibitors are potent TNF-α suppressors in LPS-stimulated human whole blood and promote efficacy in the rat adjuvant arthritis model. However, the anti-TNF-α activity of p38 inhibitors in rat whole blood has not been explored, preventing the establishment of a potential relation between in vitro and in vivo activity data in the same species. We have pharmacologically characterized a rat whole blood assay based on LPS stimulation. While p38 inhibitors showed good activity in the human assay, they failed to inhibit TNF-α in the rat whole blood assay. At high LPS concentration some compounds even potentiated TNF-α production in the rat assay, which could be reverted in the presence of the ERK pathway inhibitor U0126. Our results suggest that p38 contributes directly to TNF-α production in human whole blood while playing a negative regulatory role in rat blood which can be overridden by p38 inhibition in the presence of high stimulus concentration.
Pont-Giralt
Mercè
M
Autoimmunity Department, R&D Centre, Almirall S.A. Laureà Miró 410, Sant Feliu de Llobregat, Barcelona, Spain.
Godessart
Núria
N
Balagué
Cristina
C
D000818:Animals; D001169:Arthritis, Experimental; D002070:Butadienes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009570:Nitriles; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D048051:p38 Mitogen-Activated Protein Kinases
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