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Signal transduction pathways involved in tumour necrosis factor secretion by Plasmodium falciparum-stimulated human
1Département de Parasitologie-Mycologie Médicale et Moléculaire, CNRS, Grenoble, France.
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.
Insights
Tumour necrosis factor (TNF) is key in cerebral malaria complications. Parasite antigens activate specific cell signaling pathways, distinct from LPS, offering targets for new treatments.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Tumour necrosis factor (TNF) is implicated in cerebral malaria complications.
- Macrophage TNF secretion can be triggered by lipopolysaccharide (LPS) or Plasmodium falciparum antigens.
- The precise signaling pathways for parasite-induced TNF secretion are not fully understood.
Purpose of the Study:
- To elucidate the signal transduction pathways involved in TNF secretion induced by P. falciparum antigens.
- To compare these pathways with those activated by LPS.
- To identify potential therapeutic targets for cerebral malaria.
Main Methods:
- Utilized various inhibitors of second messenger pathways.
- Investigated the role of protein kinase C and calmodulin-dependent protein kinase.
- Examined the effect of cyclo-oxygenase inhibition (indomethacin).
- Assessed differential regulation following LPS versus parasite stimulation.
Main Results:
- Parasite antigen-induced TNF secretion involves protein kinase C and calmodulin-dependent protein kinase activation.
- Signaling pathways differ between LPS and parasite stimulation.
- Cyclo-oxygenase inhibition enhanced TNF production more with LPS than parasite stimulation.
- Parasite antigens appear to activate multiple G protein-mediated signal transduction pathways.
Conclusions:
- Signal transduction pathways for TNF secretion differ between LPS and P. falciparum antigens.
- Protein kinase C and calmodulin-dependent protein kinase are key mediators.
- Understanding these pathways is crucial for developing inhibitors against TNF overproduction in cerebral malaria.