Differential reactivity of brain microvascular endothelial cells to TNF reflects the genetic susceptibility to cerebral malaria

Article Article scientifique Article Differential reactivity of brain microvascular endothelial cells to TNF reflects the genetic susceptibility to cerebral malaria eng 1998 author Lou Jinning 26933 author Gasche Yvan 32923 author Zheng Lei 106906 author Critico Brigitte 29324 author Monso-Hinard Christine 46425 author Juillard Pierre 23685 author Morel Philippe 22337 author Buurman W A author Grau Georges 22432 3989-4000 10.1002/(SICI)1521-4141(199812)28:12<3989::AID-IMMU3989>3.0.CO;2-X 9862335 0014-2980 Upon infection with Plasmodium berghei ANKA (PbA), various inbred strains of mice exhibit different susceptibility to the development of cerebral malaria (CM). Tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma) have been shown to be crucial mediators in the pathogenesis of this neurovascular complication. Brain microvascular endothelial cells (MVEC) represent an important target of both cytokines. In the present study, we show that brain MVEC purified from CM-susceptible (CM-S) CBA/J mice and CM-resistant (CM-R) BALB/c mice exhibit a different sensitivity to TNF. CBA/J brain MVEC displayed a higher capacity to produce IL-6 and to up-regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in response to TNF than BALB/c brain MVEC. In contrast, no difference was found in the induction of E-selectin after TNF challenge. CM-S brain MVEC were also significantly more sensitive to TNF-induced lysis. This differential reactivity to TNF was further substantiated by comparing TNF receptor expression on CM-S and CM-R brain MVEC. Although the constitutive expression of TNF receptors was comparable on cells from the two origins, TNF induced an up-regulation of both p55 and p75 TNF receptors in CM-S, but not in CM-R brain MVEC. A similar regulation was found at the level of TNF receptor mRNA, but not for receptor shedding. Although a protein kinase C inhibitor blocked the response to TNF in both the brain MVEC, an inhibitor of protein kinase A selectively abolished the response to TNF in CM-R, but not CM-S brain MVEC, suggesting a differential protein kinase involvement in TNF-induced activation of CM-S and CM-R brain MVEC. These results indicate that brain MVEC purified from CM-S and CM-R mice exhibit distinctive sensitivity to TNF This difference may be partly due to a differential regulation of TNF receptors and via distinct protein kinase pathways. Animals Brain/blood supply E-Selectin/biosynthesis/immunology Endothelium, Vascular/immunology/parasitology Genetic Predisposition to Disease/immunology Intercellular Adhesion Molecule-1/biosynthesis/immunology Interleukin-6/biosynthesis/immunology Malaria, Cerebral/immunology/pathology Mice Mice, Inbred Strains Microcirculation Plasmodium berghei Species Specificity Tumor Necrosis Factor-alpha/pharmacology Vascular Cell Adhesion Molecule-1/biosynthesis/immunology Dewey 617 57 Département de chirurgie 222 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 false 79 Chirurgie viscérale 104 1329 Chirurgie viscérale (HUG) 255 Groupe Gasche Yvan (Soins intensifs) 501 European Journal of Immunology 28 12 e7e1e42a-0131-4dfc-aaa6-c8d6a08dc86f Article (Published version) Restricted 3989_ftp.pdf 211115 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences

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Differential reactivity of brain microvascular endothelial cells to TNF reflects the genetic susceptibility to cerebral malaria	European Journal of Immunology			1998	786	0

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