Signal transduction pathways involved in tumour necrosis factor secretion by Plasmodium falciparum-stimulated human monocytes

Abstract

Tumour necrosis factor (TNF) plays a pivotal role in the induction of cerebral complications during Plasmodium falciparum malaria. TNF secretion by macrophages can be induced by lipopolysaccharide (LPS) and by P. falciparum antigens, but it is unclear whether similar mechanisms control the monokine expression in both cases. The signal transduction pathway by which parasite antigens induce TNF secretion remains to be established. The results reported here, using various inhibitors of second messenger pathways, clearly demonstrate that the signal transduction leading to TNF secretion is mediated partly through protein kinase C and calmodulin-dependent protein kinase activation. Furthermore, this signal seems to be differentially regulated after LPS or parasite stimulation, since cyclo-oxygenase inhibition by indomethacin resulted in twofold more TNF production enhancement with LPS stimulation than with parasite stimulation. The nature of the receptor involved in the parasite induced-macrophage stimulation remains obscure. However, the results discussed here indicate that parasite antigens stimulate multiple signal transduction pathways via G protein. Identification of the different pathways involved in these receptor-mediated events may be invaluable in the development of specific inhibitors against TNF over-production during cerebral malaria.