Short-term interleukin-1(beta) increases the release of secreted APP(alpha) via MEK1/2-dependent and JNK-dependent alpha-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-1beta (IL-1beta) 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-1beta (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-1beta 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-1beta-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-1beta-induced-sAPP(alpha) release. Moreover, to determine whether an intracellular signaling pathway mediates the IL-1beta-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-1beta-induced-sAPP(alpha) release is dependent on MEK1/2- and JNK-activated alpha-secretase cleavage in neuroglioma U251 cells.
Ma
Guozhao
G
Department of Neurology, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China.
Chen
Shengdi
S
Wang
Xijin
X
Ba
Maowen
M
Yang
Hui
H
Lu
Guoqiang
G
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000873:Anthracenes / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005910:Glioma; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012995:Solubility; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; C432165:pyrazolanthrone; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one