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Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
In Alzheimer’s disease (AD) one finds increased deposition of A
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 (A1–40 and A1–42)-induced expression of inflammatory cytokines and chemokines. We observed that A peptides at physiological concentrations (125 nM) increased mRNA expression of cytokines (TNF-
, and IL-1) and chemokines (monocyte chemoattractant protein-1 (MCP-1), IL-8, and macrophage inflammatory protein-1 (MIP-1)). 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 A causes phosphorylation of ERK-1/ERK-2, which, in turn, activates Elk-1. Furthermore, A mediated a time-dependent increase in DNA binding activity of early growth response-1 (Egr-1) and AP-1, but not of NF-
B and CREB. Moreover, A-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 A-induced expression of TNF-, IL-1, MCP-1, IL-8, and MIP-1 was abrogated in Egr-1 small inhibitory RNA-transfected cells. Our results indicate that A-induced expression of cytokines (TNF- and IL-1) and chemokines (MCP-1, IL-8, and MIP-1) 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.
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