Published online before print June 12, 2007

This Article Full Text Free Full Text (PDF) Free All Versions of this Article: jlb.0906575v1 82/3/497    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marshall, J. D. Articles by Van Nest, G. Search for Related Content PubMed PubMed Citation Articles by Marshall, J. D. Articles by Van Nest, G.

(Journal of Leukocyte Biology. 2007;82:497-508.)
© 2007 by Society for Leukocyte Biology

Negative regulation of TLR9-mediated IFN- induction by a small-molecule, synthetic TLR7 ligand

Dynavax Technologies Corporation, Berkeley, California, USA

¹ Correspondence: Dynavax Technologies Corp., 2929 7th St., Ste. 100, Berkeley, CA 94710, USA. E-mail: jmarshall{at}dvax.com

ABSTRACT

Toll-like receptors (TLRs) are a family of molecules that function as sensors for the detection of foreign pathogens through the recognition of nonvariable microbial motifs. Although numerous studies have focused on singular TLRs, less attention has been focused on how simultaneous signaling of multiple TLRs may result in counter-regulation of the effects of each. Here, we examine the counter-regulation that occurs during simultaneous stimulation of TLR7 and TLR9 on human plasmacytoid dendritic cells (PDCs) and B cells. Interestingly, we observed that the capacity for potent IFN--induction by TLR9 ligands like CpG-C and CpG-A is markedly reduced by concurrent small molecule TLR7 stimulation. However, this inhibition is specific to particular CpG motif-containing immunostimulatory sequence (ISS) functions such as IFN- induction and BDCA-2 down-regulation. Other ISS activities such as PDC expression of CD80/CD86, secretion of IL-6, and B cell proliferation are not altered by the presence of TLR7 ligands (TLR7Ls). In concordance with the ability of TLR7Ls to decrease IFN- secretion induced by ISS, we also find that the expression of interferon regulatory factor-7 (IRF-7), a transcriptional factor critical for IFN- expression, is reduced. Furthermore, down-regulation of TLR9 mRNA expression is accelerated after TLR7 stimulation. These data indicate that TLR7 and TLR9 costimulation do not combine synergistically for IFN- induction and demonstrate that, instead, a negative feedback mechanism has evolved, possibly to prevent levels of IFN- secretion potentially detrimental to the host.

Key Words: TLR9 • TLR7 • PDCs • type I interferon

This article has been cited by other articles:

				J. S. Poovassery, T. J. Vanden Bush, and G. A. Bishop Antigen Receptor Signals Rescue B Cells from TLR Tolerance J. Immunol., September 1, 2009; 183(5): 2974 - 2983. [Abstract] [Full Text] [PDF]

				M. McCarron and D. J. Reen Activated Human Neonatal CD8+ T Cells Are Subject to Immunomodulation by Direct TLR2 or TLR5 Stimulation J. Immunol., January 1, 2009; 182(1): 55 - 62. [Abstract] [Full Text] [PDF]

				N. Sachdeva, V. Asthana, T. H. Brewer, D. Garcia, and D. Asthana Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-{alpha} but Not Proinflammatory Cytokines J. Immunol., August 15, 2008; 181(4): 2887 - 2897. [Abstract] [Full Text] [PDF]