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Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, I
B Kinase 
, and NF-B1
* Institute of Immunology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany; and
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany
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-
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- 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
B kinase 
(IKK) and NF-B, and subsequent TNF- production. Our study shows that PDE inhibition by zinc modulates the monocytic immune response by selectively intervening in the Raf-1/IKK/NF-B pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Grants Ha 4318/3-2 from Deutsche Forschungsgemeinschaft and G-2097-1400.13/2004 from the German Israeli Foundation for Scientific Research and Development.
2 Address correspondence and reprint requests to Dr. Hajo Haase, Institute of Immunology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail address: hhaase{at}ukaachen.de
3 Abbreviations used in this paper: PDE, cyclic nucleotide phosphodiesterase; sGC, soluble guanylate cyclase; PKA, protein kinase A; PKG, protein kinase G; CR, conserved region; IKK, IB kinase ; RA, rheumatoid arthritis.
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