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

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