Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

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Abstract
In Alzheimer’s disease (AD) one finds increased deposition of Aβ and also an increased presence of monocytes/macrophages in the vessel wall and activated microglial cells in the brain. AD patients show increased levels of proinflammatory cytokines by activated microglia. Here we used a human monocytic THP-1 cell line as a model for microglia to delineate the cellular signaling mechanism involved in amyloid peptides (Aβ1–40 and Aβ1–42)-induced expression of inflammatory cytokines and chemokines. We observed that Aβ peptides at physiological concentrations (125 nM) increased mRNA expression of cytokines (TNF-α, and IL-1β) and chemokines (monocyte chemoattractant protein-1 (MCP-1), IL-8, and macrophage inflammatory protein-1β (MIP-1β)). The cellular signaling involved activation of c-Raf, extracellular signal-regulated kinase-1 (ERK-1)/ERK-2, and c-Jun N-terminal kinase, but not p38 mitogen-activated protein kinase. This is further supported by the data showing that Aβ causes phosphorylation of ERK-1/ERK-2, which, in turn, activates Elk-1. Furthermore, Aβ mediated a time-dependent increase in DNA binding activity of early growth response-1 (Egr-1) and AP-1, but not of NF-κB and CREB. Moreover, Aβ-induced Egr-1 DNA binding activity was reduced >60% in THP-1 cells transfected with small interfering RNA duplexes for Egr-1 mRNA. We show that Aβ-induced expression of TNF-α, IL-1β, MCP-1, IL-8, and MIP-1β was abrogated in Egr-1 small inhibitory RNA-transfected cells. Our results indicate that Aβ-induced expression of cytokines (TNF-α and IL-1β) and chemokines (MCP-1, IL-8, and MIP-1β) in THP-1 monocytes involves activation of ERK-1/ERK-2 and downstream activation of Egr-1. The inhibition of Egr-1 by Egr-1 small inhibitory RNA may represent a potential therapeutic target to ameliorate the inflammation and progression of AD.