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

Upon infection with Plasmodium berghei ANKA (PbA), Various inbred strains o f mice exhibit different susceptibility to the development of cerebral mala ria (CM). Tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma ) have been shown to be crucial mediators in the pathogenesis of this neuro vascular complication. Brain microvascular endothelial cells (MVEC) represe nt an important target of both cytokines. In the present study, we show tha t brain MVEC purified from CM-susceptible (CM-S) CBA/J mice and GM-resistan t (CM-R) BALB/c mice exhibit a different sensitivity to TNF. CBA/J brain MV EC displayed a higher capacity to produce IL-6 and to up-regulate intercell ular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VC AM-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 M VEC were also significantly more sensitive to TNF-induced lysis. This diffe rential reactivity to TNF was further substantiated by comparing TNF recept or expression on CM-S and CM-R brain MVEC. Although the constitutive expres sion of TNF receptors was comparable on cells from the two origins, TNF ind uced 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 recept or mRNA, but not for receptor shedding. Although a protein kinase C inhibit or blocked the response to TNF in both the brain MVEC, an inhibitor of prot ein 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-i nduced 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.