Article: article from journal or magazin.
Differential regulation of tumor necrosing factor-alpha (TNF-alpha) and interleukin-10 (IL-10) secretion by protein kinase and phosphatase inhibitors in human alveolar macrophages.
European Cytokine Network
IL-10, a cytokine first identified as a product of cloned Th2 lymphocytes, is also produced by monocytes/macrophages. By its ability to inhibit cytokine synthesis and the expression of surface antigens, IL-10 is able to temper inflammation. In contrast, TNF-alpha plays a key role in acute and chronic inflammation and has been implicated in several forms of lung injury. The objective of this study was to investigate whether activators or inhibitors of LPS-activated signalling pathways might be able to dissociate TNF-alpha from IL-10 secretion in alveolar macrophages (AM). The results show that PMA activates expression of TNF-alpha without inducing IL-10 expression. We further demonstrate that LPS-induced TNF-alpha secretion is independent of PKC activation and can be increased by inhibitors of the serine/threonine phosphatases PP1 and PP2A. In contrast, LPS-mediated IL-10 secretion is down-regulated by PMA and inhibitors of PP1 and PP2A. Addition of PKC inhibitors reverses the PMA-mediated down-regulation of LPS-induced IL-10 secretion, indicating that PKC, once activated in vivo, might play a prominent role in controlling the secretion of IL-10 by AM. This study provides evidence that the PKC activator PMA and the phosphatase inhibitor calyculin A are able to dissociate TNF-alpha from IL-10 secretion by AM. Our data further indicate that LPS-mediated activation of certain signalling molecules has different consequences on the secretion of TNF-alpha or IL-10 by AM, an observation which may be important for the modulation of immune and inflammatory processes.
Cells, Cultured, Enzyme Inhibitors/pharmacology, Gene Expression Regulation/drug effects, Humans, Inflammation, Interleukin-10/biosynthesis, Interleukin-10/genetics, Lipopolysaccharides/pharmacology, Macrophages, Alveolar/drug effects, Macrophages, Alveolar/enzymology, Oxazoles/pharmacology, Phosphoprotein Phosphatases/antagonists & inhibitors, Protein Kinase C/antagonists & inhibitors, Protein Kinase Inhibitors, RNA, Messenger/biosynthesis, Signal Transduction, Tetradecanoylphorbol Acetate/pharmacology, Tumor Necrosis Factor-alpha/secretion
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