Plasmodium falciparum glycosylphosphatidylinositol-induced TNF-alpha secretion by macrophages is mediated without membrane insertion or endocytosis

The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are belie ved to contribute to the pathogenesis of malaria by inducing the secretion of proinflammatory cytokines by macrophages, Previous studies have shown th at P, falciparum GPIs elicit toxic immune responses by protein tyrosine kin ase (PTK)- and protein kinase C (PKC)-mediated cell signaling pathways, whi ch are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-alpha by P, falc iparum GPIs in macrophages is mediated by the recognition of the distal fou rth mannose residue. This event is critical but not sufficient for the prod uctive cell signaling; interaction by the acylglycerol moisty of GPIs is al so required. These novel interactions are coupled to previously demonstrate d PTK and PKC pathways, since the specific inhibitors of these kinases effe ctively blocked the GPI-induced TMF-alpha: production. Surprisingly, sn-2 l yso-GPIs were also able to elicit TNF-alpha secretion. Contrary to the prev ailing notion, GPIs are neither inserted to the plasma membranes nor endocy tosized, Thus, this study defines the GPI structural requirements and revea ls a novel mechanism for the outside-in activation of cell signaling by P, falciparum GPIs in inducing proinflammatory responses.