Interleukin‐1α stimulates non‐amyloidogenic pathway by α‐secretase (ADAM‐10 and ADAM‐17) cleavage of APP in human astrocytic cells involving p38 MAP kinase

AbstractInterleukin‐1α (IL‐1α) stimulates a disintegrin and metalloproteinase, ADAM‐17 synthesis, consistent with activation of the soluble fragment of Amyloid Precursor Protein, APP, (sAPPα) in human primary astrocytes. To characterize the mechanism by which IL‐1α promotes the non‐amyloidogenic pathway of APP metabolism, we used U373 MG astrocytoma cells. IL‐1α significantly increased levels of ADAM‐10 and ADAM‐17 mRNA in 16 hr. Upregulation of ADAM‐17 mRNA by IL‐1α was more pronounced despite higher basal levels of ADAM‐10 mRNA. This pattern was also observed at the protein level with the upregulation of α‐secretase. RNA interference (RNAi) of ADAM‐10 and ADAM‐17 inhibited IL‐1α‐stimulated sAPPα release and the effect was more pronounced with ADAM‐17 RNAi. Concomitantly, the level of sAPPα was significantly increased by IL‐1α in 48 hr; however, IL‐1α stimulated cell‐associated APP levels maximally at 6 h but the induction declined at 48 hr. IL‐1α treatment of cells for 48 h reduced both intracellular and secreted levels of amyloid‐β, Aβ‐40, and Aβ‐42 peptides. Multiple MAP kinases (MAPK), including MEK/ERK, p38 kinase, PI3 kinase (PI3K) but not JNK were involved in the regulation of IL‐1α‐stimulated α‐secretase activity and sAPPα release. p38 MAPK seems to be the most proximal of these MAPKs, as it was the earliest to be activated by IL‐1α and blocking this pathway attenuated activation of IL‐1α‐induced MEK and PI3K pathways. Our data show a complex mechanism of sAPPα regulation by IL‐1α that involves ADAM‐10, ADAM‐17 and p38 MAPK upstream of MEK and PI3K. © 2006 Wiley‐Liss, Inc.