Extended sequence preferences for oligodeoxyribonucleotide activity

Petar Lenert; Adam J Goeken; Robert F Ashman

doi:10.1111/j.1365-2567.2006.02320.x

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Extended sequence preferences for oligodeoxyribonucleotide activity

Journal article

Open access

Peer reviewed

Extended sequence preferences for oligodeoxyribonucleotide activity

Petar Lenert, Adam J Goeken and Robert F Ashman

Immunology, Vol.117(4), pp.474-481

04/2006

DOI: 10.1111/j.1365-2567.2006.02320.x

PMCID: PMC1782261

PMID: 16556261

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Abstract

Synthetic type B phosphorothioate oligodeoxyribonucleotides (ODN) activate mouse B cells via Toll-like receptor 9 (TLR9). Starting with closely related 15-mer prototype ODN, the sequence requirements for stimulatory (ST-) and inhibitory (IN-) activity were contrasted, by measuring apoptosis protection, G(1) entry and interleukin-6 secretion. ST-ODN and IN-ODN differ in that (1) ST-ODN require a 5' T, (2) the central CG is obligatory, (3) CG must be flanked 3' specifically by TT at the position where IN-ODN have GG, and (4) IN-ODN tolerate truncation of the 3' end better than ST-ODN. Features shared by ST-ODN and IN-ODN include (1) requiring CC adjacent to the 5' end, and (2) avoiding CC immediately 5' to the CG. This pattern is used to create a model of how ST-ODN binding might function to aggregate TLR9 so as to initiate the signal, and how the 5' ends of ST-ODN and IN-ODN compete for binding. Further justification for considering TLR9 to be the ODN receptor was provided by a demonstration that in HEK293 cells transfected with TLR9, the potency of a panel of ODN for activating NF-kappaB roughly parallels that seen in the biological assays in mouse B cells.

G1 Phase - immunology

CpG Islands - immunology

DNA-Binding Proteins - immunology

Dose-Response Relationship, Immunologic

Oligodeoxyribonucleotides - immunology

Cells, Cultured

NF-kappa B - metabolism

Structure-Activity Relationship

Mice, Inbred Strains

Toll-Like Receptor 9 - immunology

Animals

Apoptosis - immunology

B-Lymphocytes - immunology

Oligodeoxyribonucleotides - genetics

Base Sequence

Female

Mice

Interleukin-6 - metabolism

Details

Title: Subtitle: Extended sequence preferences for oligodeoxyribonucleotide activity
Creators: Petar Lenert - Division of Rheumatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. petar-lenert@uiowa.edu
Adam J Goeken
Robert F Ashman
Resource Type: Journal article
Publication Details: Immunology, Vol.117(4), pp.474-481
DOI: 10.1111/j.1365-2567.2006.02320.x
PMID: 16556261
PMCID: PMC1782261
NLM abbreviation: Immunology
ISSN: 0019-2805
eISSN: 1365-2567
Grant note: R01 AI047374 / NIAID NIH HHS R01AI047374 / NIAID NIH HHS
Language: English
Date published: 04/2006
Academic Unit: Pathology; Immunology; Internal Medicine
Record Identifier: 9984094614702771

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