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

✍ Scribed by Guozhao Ma; Shengdi Chen; Xijin Wang; Maowen Ba; Hui Yang; Guoqiang Lu

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 308 KB
• Volume: 80
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.20515

✦ Synopsis

Abstract

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‐1β (IL‐1β) to regulate the processing of beta‐amyloid precursor protein (β‐APP) in neuroglioma U251 cells. Our findings have shown that short‐term treatment with IL‐1β (2 hr) resulted in a concentration‐dependent decrease in the amount of the cell‐associated form of β‐APP in U251 cells as compared to untreated cells, whereas a 2‐hr treatment with IL‐1β led to increased release of secreted APPα fragment (sAPPα) into the conditioned media of the cells. The fact that sAPPα is an α‐secretase cleavage metabolite of the cell‐associated form of β‐APP, and the observation that IL‐1β‐induced sAPPα release could be blocked by tissue inhibitors of metalloproteinases‐1 (α‐secretase inhibitors), suggested that α‐secretase might be involved in IL‐1β‐induced‐sAPPα release. Moreover, to determine whether an intracellular signaling pathway mediates the IL‐1β‐induced increase in sAPPα secretion, we used various specific signaling inhibitors and found that sAPPα 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‐1β‐induced‐sAPPα release is dependent on MEK1/2‐ and JNK‐activated α‐secretase cleavage in neuroglioma U251 cells. © 2005 Wiley‐Liss, Inc.