Differential regulation of tumor necrosing factor-alpha (TNF-alpha) and interleukin-10 (IL-10) secretion by protein kinase and phosphatase inhibitorsin human alveolar macrophages

IL-10, a cytokine first identified as a product of cloned Th2 lymphocytes, is also produced by monocytes/macrophages. By its ability to inhibit cytoki ne synthesis and the expression of surface antigens, IL-10 is able to tempe r inflammation. In contrast, TNF-alpha plays a key role in acute and chroni c inflammation and has been implicated in several forms of lung injury, The objective of this study was to investigate whether activators or inhibi tors of LPS-activated signalling pathways might be able to dissociate TNF-a lpha from IL-10 secretion in alveolar macrophages (AM), The results show th at 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/threoni ne 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 inhib itors reverses the PMA-mediated down-regulation of LPS-induced IL-10 secret ion, indicating that PKC, once activated in vivo, might play a prominent ro le 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 secretio n by AM. Our data further indicate that LPS-mediated activation of certain signalling molecules has different consequences on the secretion of TNF-alp ha or IL-10 by AM, an observation which may be important for the modulation of immune and inflammatory processes.