Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans

It is now generally accepted that IFN-gamma, secreted by Th1 cells, is the most potent cytokine leading to macrophage activation and host resistance a gainst infection with the intracellular protozoan parasite Leishmania. It i s also established that IL-12 is a critical cytokine involved in the differ entiation and expansion of Th1 cells. Therefore, the ability of Leishmania para sites to actively suppress IL-12 production by host macrophages may be an important strategy for parasite survival. Here we report that a major p arasite cell surface molecule, phosphoglycan (PG), of Leishmania could sele ctively inhibit the synthesis of IL-12(p40, p70) by activated murine macrop hages. Furthermore, synthetic PG (sPG) was able to inhibit IL-12 release in a dose-dependent manner. Inhibition was dependent on the galactose(beta 1- 4)mannose(alpha 1)-PO4 repeating units and not the glycophosphoinositol lip id anchor of lipo-phosphoglycan. Al the concentration used, sPG had no effe ct on the release of TNF-alpha or IL-6 in activated macrophages. The inhibi tion of IL-12(p40) production was at the transcriptional level, but was not mediated through NF kappa B inhibition. These data demonstrate that PG may be an important molecule for the establishment and survival of the parasit e in permissive hosts.