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Glycosylphosphatidylinositols (GPIs) are the most abundant molecules present in the membranes of the parasitic protozoa Leishmania responsible for multiple forms of leishmaniasis. Among the prominent biological activities displayed by the major Leishmania GPIs [lipophosphoglycan (LPG) and glycoinositolphospholipids (GIPLs)] is the inhibition of macrophage functions such as the protein kinase C (PKC)-dependent signaling pathway. The bioactivity of Leishmania GPIs is in contrast to Trypanosoma brucei and Plasmodium falciparum GPIs, which activate the macrophage functions. To address the question as to which structural domain of Leishmania GPIs is responsible for dramatic down-regulation of PKC-dependent transient c-fos expression, the chemically synthesized defined alkylacylglycerolipids domain of corresponding GPIs, and LPG and GIPLs isolated from Leishmania donovani, were evaluated for inhibition of PKC and c-fos expression in macrophages.The results presented here demonstrate that the unusual lipid domain of Leishmania GPIs is primarily responsible for inhibition of PKC-dependent transient c-fos expression.