A cyclic adenosine 3',5'-monophosphate signal is required for the induction of IL-1 beta by TNF-alpha in human monocytes.
IL-1 beta is a cytokine generally considered to be a major component involved in the pathogenesis of rheumatoid arthritis and other inflammatory diseases. Of the agents found in high concentrations in inflamed rheumatoid arthritis joints, TNF-alpha is among the most strongly implicated as an in vivo inducer of IL-1 beta. Here we report that in human PBMC and in a stable transfectant of the promonocytic cell line, THP-1, TNF-alpha indeed appears to be an inducer of IL-1 beta production, but only in the presence of dibutyryl cAMP or agents such as the PG that elevate intracellular cAMP levels. This TNF-alpha/cAMP pathway regulates IL-1 beta production at the level of transcription and requires a cAMP response element located between -2762 and -2755 bp in the upstream regulatory sequence of IL-1 beta. Because PG, which are known to elevate cAMP levels in vivo, and TNF-alpha are both found in significant quantities in the synovial fluid of rheumatoid arthritis joints, the observed synergistic up-regulation in IL-1 beta synthesis by TNF-alpha/cAMP (PG) may provide valuable insight into the potential pathways involved in the continuous production of IL-1 beta in the chronically inflamed joint.
Lorenz
J J
JJ
Department of Cell Physiology, Glaxo Wellcome, Inc., Research Triangle Park, NC 27709, USA.
Furdon
P J
PJ
Taylor
J D
JD
Verghese
M W
MW
Chandra
G
G
Kost
T A
TA
Haneline
S A
SA
Roner
L A
LA
Gray
J G
JG
D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000737:chemistry; D001483:Base Sequence; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D003994:Bucladesine; D000242:Cyclic AMP; D000469:Alkaline Phosphatase