Zinc-dependent suppression of TNF-alpha production is mediated by protein kinase A-induced inhibition of Raf-1, I kappa B kinase beta, and NF-kappa B.
Excessive and permanent cytokine production in response to bacterial LPS causes cell and tissue damage, and hence organ failure during sepsis. We have previously demonstrated that zinc treatment prevents LPS-induced TNF-alpha expression and production in human monocytes by inhibiting cyclic nucleotide phosphodiesterase (PDE) activity and expression, and subsequent elevation of the cyclic nucleotide cGMP. In the present study, we investigated the molecular mechanism by which cGMP signaling affects the LPS-induced signaling cascade to suppress TNF-alpha transcription and release from monocytes. Zinc-mediated cGMP elevation led to cross activation of protein kinase A. This zinc-induced protein kinase A activation inhibited Raf-1 activity by phosphorylation at serine 259, preventing activation of Raf-1 by phosphorylation of serine 338. By this mechanism, zinc suppressed LPS-induced activation of IkappaB kinase beta (IKKbeta) and NF-kappaB, and subsequent TNF-alpha production. Our study shows that PDE inhibition by zinc modulates the monocytic immune response by selectively intervening in the Raf-1/IKKbeta/NF-kappaB pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.
von Bülow
Verena
V
Institute of Immunology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Dubben
Svenja
S
Engelhardt
Gabriela
G
Hebel
Silke
S
Plümäkers
Birgit
B
Heine
Holger
H
Rink
Lothar
L
Haase
Hajo
H
D000818:Animals; D002413:Cations, Divalent; D002460:Cell Line; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015032:Zinc / Q000502:physiology*