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

ABSTRACT

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