title: Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production.
abstract: The proinflammatory cytokine interleukin (IL)-1beta is up-regulated in microglial cells surrounding amyloid plaques, leading to the hypothesis that IL-1beta is a risk factor for Alzheimer's disease. However, we unexpectedly found that IL-1beta significantly enhanced alpha-cleavage, indicated by increases in sAPPalpha and C83, but reduced beta-cleavage, indicated by decreases in sAPPbeta and Abeta40/42, in human neuroblastoma SK-N-SH cells. IL-1beta did not significantly alter the mRNA levels of BACE1, ADAM-9, and ADAM-10, but up-regulated that of TACE by threefold. The proform and mature form of TACE protein were also significantly up-regulated. A TACE inhibitor (TAPI-2) concomitantly reversed the IL-1beta-dependent increase in sAPPalpha and decrease in sAPPbeta, suggesting that APP consumption in the alpha-cleavage pathway reduced its consumption in the beta-cleavage pathway. IL-1Ra, a physiological antagonist for the IL-1 receptor, reversed the effects of IL-1beta, suggesting that the IL-1beta-dependent up-regulation of alpha-cleavage is mediated by the IL-1 receptor. IL-1beta also induced this concomitant increase in alpha-cleavage and decrease in beta-cleavage in mouse primary cultured neurons. Taken together we conclude that IL-1beta is an anti-amyloidogenic factor, and that enhancement of its signaling or inhibition of IL-1Ra activity could represent potential therapeutic strategies against Alzheimer's disease.
authors.affiliation: Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, The Institute of Physical and Chemical Research (RIKEN), Saitama, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Tachida
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Takashi
authors.initials: T
authors.lastname: Honda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D006868:Hydrolysis; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053583:Interleukin-1beta; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse