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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 26, 2005; DOI: 10.1124/jpet.105.084004

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Joseph J Senn
Sebastien Burel
Scott P Henry
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Received for publication February 1, 2005.
Revised May 19, 2005.
Accepted for publication May 23, 2005.

Non-CpG Containing Antisense 2' MOE Oligonucleotides Activate a Proinflammatory Response Independent of TLR-9 or MyD88

Joseph J Senn 1, Sebastien Burel 1, Scott P Henry 2*

1 ISIS Pharmaceuticals, Inc. 2 Isis Pharmaceuticals, Inc.

* Address correspondence to: E-mail: shenry{at}isisph.com

Abstract

Oligonucleotides with a "CpG" motif trigger a proinflammatory response through activation of Toll-like receptor 9 (TLR9) and are being studied to exploit these properties for use as adjuvants and cancer therapies. However, oligonucleotides intended for antisense applications (ASOs) are designed to minimize proinflammatory responses by avoiding CpG motifs and using chemical modifications (i.e., 2'-methoxyethyl sugars and 5-methyl cytosine residues). Nonetheless, modified ASOs are capable of eliciting a proinflammatory response at high doses, albeit mild compared to CpG oligos. To determine if this phenomena is TLR-mediated, wild type, TLR9 knockout and MyD88 knockout mice were treated with a PS ODN CpG optimal oligo (ISIS 12449), and a representative non-CpG 2' MOE oligonucleotide (ISIS 116847). The non-CpG oligonucleotide, had a lower proinflammatory potency relative to ISIS 12449, requiring a >10-fold higher dose in wild-type animals to trigger a proinflammatory response. Furthermore, the inflammatory response to ISIS 12449 at low doses was TLR9 and MyD88-dependent while, non-CpG oligonucleotides retained the ability to activate a proinflammatory response in the knockout animals. Animals treated with the non-CpG oligonucleotide exhibited an increased spleen weight, elevated cytokine levels, increased immune cell infiltrates in liver and an increased level of mRNA for cell surface markers typical of monocyte/macrophage type cells. Bone marrow-derived cells from wild-type and knockout animals treated with non-CpG oligonucleotide responded similarly with the production of MIP-2 and the activation of ERK 1/2. These data implicate a TLR independent mechanism of activation for non-CpG 2' MOE oligonucleotides.


Key words: Chemokine, Inflamation, Mouse, Oligonucleotide, Toll-like receptor, proinflamatory


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