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
von Bülow, V.; Dubben, S.; Engelhardt, G.; Hebel, S.; Plümäkers, B.; Heine, H.; Rink, L.; Haase, H.
Journal of Immunology 179(6): 4180-4186
2007
ISSN/ISBN: 0022-1767 PMID: 17785857 Document Number: 612755
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-a 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 I kappa B kinase beta (IKK beta) and NF-kappa B, 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/IKK beta/NF-kappa B pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.