Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level

P Young; P McDonnell; D Dunnington; A Hand; J Laydon; J Lee

doi:10.1007/BF01972723

Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level

Agents Actions. 1993:39 Spec No:C67-9. doi: 10.1007/BF01972723.

Authors

P Young¹, P McDonnell, D Dunnington, A Hand, J Laydon, J Lee

Affiliation

¹ Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.

PMID: 8273589
DOI: 10.1007/BF01972723

Abstract

The mechanism by which SK&F 86002 and other pyridinyl imidazoles inhibit the production of IL-1 and TNF from LPS-stimulated human monocytes was examined. Inhibition of IL-1 and TNF production was found to depend on the time of addition of SK&F 86002, with diminishing effect when added more than 2 h after LPS stimulation. Analysis of Western blots confirmed that both intracellular IL-1 beta and extracellular TNF were significantly reduced in response to SK&F 86002, but these reductions were not paralleled by changes in IL-1 and TNF mRNA. 35S methionine pulse and pulse-chase studies on IL-1 biosynthesis suggest that significant inhibition by SK&F 86002 and related compounds occurs at the translational level.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Humans
Imidazoles / pharmacology*
Interleukin-1 / biosynthesis*
Interleukin-1 / genetics
Lipopolysaccharides / toxicity
Monocytes / drug effects*
Monocytes / metabolism
Protein Biosynthesis / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Thiazoles / pharmacology*
Tumor Necrosis Factor-alpha / biosynthesis*
Tumor Necrosis Factor-alpha / genetics

Substances

Anti-Inflammatory Agents, Non-Steroidal
Imidazoles
Interleukin-1
Lipopolysaccharides
RNA, Messenger
Thiazoles
Tumor Necrosis Factor-alpha
6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole