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Molecular and Cellular Biology, July 2008, p. 4507-4519, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.00308-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Single-Stranded Oligonucleotides Can Inhibit Cytokine Production Induced by Human Toll-Like Receptor 3{triangledown} ,{dagger}

C. T. Ranjith-Kumar,1,{ddagger} K. E. Duffy,2,{ddagger} J. L. Jordan,2 A. Eaton-Bassiri,2,¶ Robert Vaughan,1 Scott A. Hoose,1 Roberta J. Lamb,2 R. T. Sarisky,2* and C. Cheng Kao1*

Department of Biochemistry and Biophysics, Department of Chemistry, Texas A&M University, College Station, Texas 77843,1 Discovery Research, Centocor Research and Development, Inc., Radnor, Pennsylvania 190872

Received 22 February 2008/ Returned for modification 25 March 2008/ Accepted 6 May 2008

Toll-like receptor 3 (TLR3) can signal the production of a suite of cytokines and chemokines in response to double-stranded RNA (dsRNA) ligands or the dsRNA mimic poly(I-C). Using a human embryonic kidney 293T cell line to express human TLR3, we determined that poly(I-C)-induced signal could be significantly inhibited by single-stranded DNAs (ssDNAs), but not ssRNA or dsDNA. The ssDNA molecules that down-modulated TLR3 signaling did not affect TLR4 and do not require the hypomethylated CpG motif found in TLR9 ligands. The degree of modulation can be altered by the length, base sequence, and modification state of the ssDNAs. An inhibitory ssDNA was found to colocalize with TLR3 in transfected cells and in a cell line that naturally expresses TLR3. The inhibitory ssDNAs can compete efficiently with dsRNA for binding purified TLR3 ectodomains in vitro, while noninhibitory nucleic acids do not. The ssDNAs also decrease the levels of several cytokines produced by the human bronchial epithelial cell line BEAS-2B and by human peripheral blood mononuclear cells in response to poly(I-C) stimulation of native TLR3. These activities indicate that ssDNAs could be used to regulate the inflammatory response through TLR3.

* Corresponding author. Mailing address for C. Cheng Kao: Department of Biochemistry and Biophysics, Mail Stop 2128, Texas A&M University, College Station, TX 77843. Phone: (979) 845-2235. Fax: (979) 845-9274. E-mail: Ckao{at}tamu.edu. Mailing address for R. T. Sarisky: Discovery Research, Centocor Research and Development, Inc., Radnor, PA 19087. Phone: (610) 240-8777. Fax: (610) 889-4623. E-mail: RSarisky{at}cntus.jnj.com

{triangledown} Published ahead of print on 19 May 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These two authors contributed equally to this work.

Present address: GlaxoSmithKline, Collegeville, PA.

Molecular and Cellular Biology, July 2008, p. 4507-4519, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.00308-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ranjith-Kumar, C. T., Murali, A., Dong, W., Srisathiyanarayanan, D., Vaughan, R., Ortiz-Alacantara, J., Bhardwaj, K., Li, X., Li, P., Kao, C. C. (2009). Agonist and Antagonist Recognition by RIG-I, a Cytoplasmic Innate Immunity Receptor. J. Biol. Chem. 284: 1155-1165 [Abstract] [Full Text]  


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