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Int. J. Mol. Sci. 2016, 17(2), 242; doi:10.3390/ijms17020242

Synthetic Human TLR9-LRR11 Peptide Attenuates TLR9 Signaling by Binding to and thus Decreasing Internalization of CpG Oligodeoxynucleotides

1
Department of Pharmacology, College of Pharmacy, the Third Military Medical University, Chongqing 400038, China
2
Medical Research Center, Southwestern Hospital, the Third Military Medical University, Chongqing 400038, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Received: 4 October 2015 / Revised: 4 December 2015 / Accepted: 22 January 2016 / Published: 22 February 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Toll-like receptor (TLR) 9 is an endosomal receptor recognizing bacterial DNA/CpG-containing oligodeoxynucleotides (CpG ODN). Blocking CpG ODN/TLR9 activity represents a strategy for therapeutic prevention of immune system overactivation. Herein, we report that a synthetic peptide (SP) representing the leucine-rich repeat 11 subdomain of the human TLR9 extracellular domain could attenuate CpG ODN/TLR9 activity in RAW264.7 cells by binding to CpG ODN and decreasing its internalization. Our results demonstrate that preincubation with SP specifically inhibited CpG ODN- but not lipopolysaccharide (LPS)- and lipopeptide (PAM3CSK4)-stimulated TNF-α and IL-6 release. Preincubation of SP with CpG ODN dose-dependently decreased TLR9-driven phosphorylation of IκBα and ERK and activation of NF-κB/p65. Moreover, SP dose-dependently decreased FAM-labeled CpG ODN internalization, whereas non-labeled CpG ODN reversed the inhibition. The KD value of SP-CpG ODN binding was within the micromolar range. Our results demonstrated that SP was a specific inhibitor of CpG ODN/TLR9 activity via binding to CpG ODN, leading to reduced ODN internalization and decreased activation of subsequent pathways within cells. Thus, SP could be used as a potential CpG ODN antagonist to block TLR9 signaling. View Full-Text
Keywords: CpG oligodeoxynucleotides; TLR9; Toll-like receptor 9; synthetic peptide; proinflammatory cytokine; nuclear factor; phosphorylation; internalization CpG oligodeoxynucleotides; TLR9; Toll-like receptor 9; synthetic peptide; proinflammatory cytokine; nuclear factor; phosphorylation; internalization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Pan, X.; Li, B.; Kuang, M.; Liu, X.; Cen, Y.; Qin, R.; Ding, G.; Zheng, J.; Zhou, H. Synthetic Human TLR9-LRR11 Peptide Attenuates TLR9 Signaling by Binding to and thus Decreasing Internalization of CpG Oligodeoxynucleotides. Int. J. Mol. Sci. 2016, 17, 242.

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