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Infection and Immunity, November 2005, p. 7290-7296, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7290-7296.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Effects of Forskolin on Kupffer Cell Production of Interleukin-10 and Tumor Necrosis Factor Alpha Differ from Those of Endogenous Adenylyl Cyclase Activators: Possible Role for Adenylyl Cyclase 9

Maria K. Dahle,^* Anders E. Myhre, Ansgar O. Aasen, and Jacob E. Wang

University of Oslo, Faculty Division Rikshospitalet, Institute for Surgical Research, Oslo N-0027, Norway

Received 25 December 2004/ Returned for modification 27 April 2005/ Accepted 29 July 2005

Proinflammatory cytokines like tumor necrosis factor alpha (TNF-) that are released from Kupffer cells may trigger liver inflammation and damage. Hence, endogenous mechanisms for limiting TNF- expression are crucial for avoiding the development of sepsis. Such mechanisms include the anti-inflammatory actions of interleukin-10 (IL-10) as well as signaling induced by the intracellular second messenger cyclic AMP (cAMP). Kupffer cells express several receptors that activate cAMP synthesis, including E-prostanoid receptors and ß-adrenergic receptors. The expression and role of specific adenylyl cyclases in the inhibition of Kupffer cell activation have so far not been subject to study. Pretreatment of rat Kupffer cell cultures with cAMP analogues [8-(4-chlorophenyl)-thio-cAMP], adenylyl cyclase activator (forskolin), or ligands for G-coupled receptors (isoproterenol or prostaglandin E₂) 30 min before the addition of lipopolysaccharide (LPS) (1 µg/ml) caused attenuated TNF- levels in culture medium (forskolin/isoproterenol, P 0.05; prostaglandin E₂, P 0.01). Forskolin also reduced IL-10 mRNA and protein (P 0.05), which was not observed with the other cAMP-inducing agents. Furthermore, we found that rat Kupffer cells express high levels of the forskolin-insensitive adenylyl cyclase 9 compared to whole liver and that this expression is down-regulated by LPS (P 0.05). We conclude that regulation of TNF- and IL-10 in Kupffer cells depends on the mechanism by which cAMP is elevated. Forskolin and prostaglandin E₂ differ in their effects, which suggests a possible role of forskolin-insensitive adenylyl cyclases like adenylyl cyclase 9.

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* Corresponding author. Mailing address: University of Oslo, Faculty Division Rikshospitalet, Institute for Surgical Research, Oslo N-0027, Norway. Phone: 47 23071404. Fax: 47 23073530. E-mail: m.k.dahle{at}medisin.uio.no.

Editor: J. L. Flynn

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Infection and Immunity, November 2005, p. 7290-7296, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7290-7296.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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