Inflammatory protein sPLA2-IIA abrogates TNFα-induced apoptosis in human astroglioma cells: Crucial role of ERK

Abstract

Brain injury induces the expression of well-known cytokines, such as tumor necrosis factor-alpha (TNF alpha), and other, which functions are less understood, as secreted phospholipase A(2) group IIA (sPLA(2)-IIA). Since in pathological processes, cytokines function coordinately in networks, to further explore the actions Of sPLA(2)-IIA in tumorigenesis, we investigated the effect Of sPLA(2)-IIA in the presence of TNF alpha in human 1321N1 astrocytoma cells. In these cells, TNF alpha activates the apoptotic programme that is accompanied of cytoskeleton changes; however, simultaneous treatment with sPLA(2)-IIA prevents TNF alpha-mediated apoptosis and reverses the modification of the markers associated to this response. In fact, the mitogenic activity elicited by the phospholipase alone is preserved. This inhibitory effect is not found in other TNFa-mediated responses, even a functional cooperation is observed on COX-2 protein induction. The cross-talk between TNF alpha and sPLA(2)-IIA is associated with ERK activity since its pharmacological inhibition attenuates both synergistic and inhibitory responses. We have also observed that upon sPLA(2)-IIA stimulation, endogenous ERK has the capacity to bind and phosphorylate sequences present within the cytoplasmic domain of TNFR1 / CD120a. These findings thus indicate that sPLA(2)-IIA and TNF alpha transduction pathways interact to modulate inflammatory responses and provide additional insights about the capacity Of sPLA(2)-IIA to promote apoptosis resistance in astrocytoma cells.