Short-term interleukin-1β increases the release of secreted APPα via MEK1/2-dependent and JNK-dependent α-secretase cleavage in neuroglioma U251 cells

Several lines of neuroimmunological evidence correlate the development of the inflammatory responses of the brain with the formation of amyloid plaques associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context, we tested the ability of interleukin-1 beta (IL-1 beta) to regulate the processing of beta-amyloid precursor protein (beta-APP) in neuroglioma U251 cells. Our findings have shown that short-term treatment with IL-1 beta (2 hr) resulted in a concentration-dependent decrease in the amount of the cell-associated form of beta-APP in U251 cells as compared to untreated cells, whereas a 2-hr treatment with IL-1 beta led to increased release of secreted APP alpha fragment (sAPP alpha) into the conditioned media of the cells. The fact that sAPP alpha is an alpha-secretase cleavage metabolite of the cell-associated form of beta-APP, and the observation that IL-1 beta-induced sAPP alpha release could be blocked by tissue inhibitors of metalloproteinases-1 (alpha-secretase inhibitors), suggested that alpha-secretase might be involved in IL-1 beta-incluced-sAPP alpha release. Moreover, to determine whether an intracellular signaling pathway mediates the IL-1 beta-induced increase in sAPP alpha secretion, we used various specific signaling inhibitors and found that sAPP alpha release is significantly blocked by the mitogen-activated protein kinase (MEK1/2) inhibitor PD98059 and the c-Jun N-terminal kinase inhibitor SP600125. These findings suggested that the mechanism of IL-1 beta-induced-sAPP alpha release is dependent on MEK1/2- and JNK-activated alpha-secretase cleavage in neuroglioma U251 cells. (c) 2005 Wiley-Liss, Inc.