PMID- 12734378 OWN - NLM STAT- MEDLINE DCOM- 20030826 LR - 20211203 IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 170 IP - 10 DP - 2003 May 15 TI - 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. PG - 5281-94 AB - In Alzheimer's disease (AD) one finds increased deposition of A beta 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 (A beta(1-40) and A beta(1-42))-induced expression of inflammatory cytokines and chemokines. We observed that A beta peptides at physiological concentrations (125 nM) increased mRNA expression of cytokines (TNF-alpha, and IL-1 beta) and chemokines (monocyte chemoattractant protein-1 (MCP-1), IL-8, and macrophage inflammatory protein-1 beta (MIP-1 beta)). 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 beta causes phosphorylation of ERK-1/ERK-2, which, in turn, activates Elk-1. Furthermore, A beta mediated a time-dependent increase in DNA binding activity of early growth response-1 (Egr-1) and AP-1, but not of NF-kappa B and CREB. Moreover, A beta-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 beta-induced expression of TNF-alpha, IL-1 beta, MCP-1, IL-8, and MIP-1 beta was abrogated in Egr-1 small inhibitory RNA-transfected cells. Our results indicate that A beta-induced expression of cytokines (TNF-alpha and IL-1 beta) and chemokines (MCP-1, IL-8, and MIP-1 beta) 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. FAU - Giri, Ranjit K AU - Giri RK AD - Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA. FAU - Selvaraj, Suresh K AU - Selvaraj SK FAU - Kalra, Vijay K AU - Kalra VK LA - eng GR - P01AG16233/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Amyloid beta-Peptides) RN - 0 (Anthracenes) RN - 0 (Chemokines) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Cytokines) RN - 0 (DNA-Binding Proteins) RN - 0 (EGR1 protein, human) RN - 0 (Early Growth Response Protein 1) RN - 0 (Flavonoids) RN - 0 (Immediate-Early Proteins) RN - 0 (NF-kappa B) RN - 0 (Nucleic Acid Heteroduplexes) RN - 0 (Peptide Fragments) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (Transcription Factor AP-1) RN - 0 (Transcription Factors) RN - 0 (amyloid beta-protein (1-40)) RN - 0 (amyloid beta-protein (1-42)) RN - 1TW30Y2766 (pyrazolanthrone) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) SB - IM MH - Amyloid beta-Peptides/antagonists & inhibitors/*pharmacology MH - Anthracenes/pharmacology MH - Cells, Cultured MH - Chemokines/antagonists & inhibitors/*biosynthesis/blood/metabolism MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Cytokines/antagonists & inhibitors/*biosynthesis/blood/metabolism MH - DNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism/*physiology MH - Early Growth Response Protein 1 MH - Flavonoids/pharmacology MH - Gene Expression Regulation/drug effects/immunology MH - Humans MH - Immediate-Early Proteins/genetics/physiology MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism/physiology MH - Monocytes/enzymology/immunology/*metabolism MH - NF-kappa B/metabolism MH - Nucleic Acid Heteroduplexes/*physiology MH - Peptide Fragments/antagonists & inhibitors/*pharmacology MH - Phosphatidylinositol 3-Kinases/physiology MH - *Protein Serine-Threonine Kinases MH - Proto-Oncogene Proteins/physiology MH - Proto-Oncogene Proteins c-akt MH - Proto-Oncogene Proteins c-raf/antagonists & inhibitors/physiology MH - RNA, Messenger/biosynthesis/*physiology MH - RNA, Small Interfering/*physiology MH - Transcription Factor AP-1/genetics/metabolism MH - Transcription Factors/antagonists & inhibitors/genetics/metabolism/*physiology MH - Transcriptional Activation/drug effects MH - Tumor Cells, Cultured EDAT- 2003/05/08 05:00 MHDA- 2003/08/27 05:00 CRDT- 2003/05/08 05:00 PHST- 2003/05/08 05:00 [pubmed] PHST- 2003/08/27 05:00 [medline] PHST- 2003/05/08 05:00 [entrez] AID - 10.4049/jimmunol.170.10.5281 [doi] PST - ppublish SO - J Immunol. 2003 May 15;170(10):5281-94. doi: 10.4049/jimmunol.170.10.5281.