Small molecule analogues of an immunomodulatory helminth product provide a novel approach to dissecting macrophage signal transduction pathways: Poster abstract

ES-62 is an immunomodulatory phosphorylcholine (PC)-containing protein that is actively secreted by the rodent filarial nematode Acanthocheilonema viteae during parasitism of the vertebrate host. The net effect of ES-62¢s interaction with the immune system is the generation of an anti-inflammatory immunological phenotype. ES-62 acts to inhibit the inflammatory response by selectively targeting key MAPkinase and NF-jB signalling cassettes in a number of cells of the immune system. The activity of ES-62 is dependent on its PC moieties and therefore we tested a range of small PC-containing compounds for comparable
activity to the parent molecule, in in vitro assays of inflammation employing mouse macrophages. Some of the compounds examined were indeed found to mimic the anti-inflammatory effects of ES-62 but of particular interest was the observation that some selectivity of action was demonstrated, with certain compounds differentially inhibiting distinct functional components of the inflammatory response. This raises the exciting possibility of employing such small compounds to dissect the network of key signalling pathways underlying immune cell responsiveness. In particular, we are focusing on molecular signals involved in differentially regulating inflammatory cytokines including IL-12p40, TNF-a and IL-6 produced by macrophages.