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Cutting Edge: Differential Inhibition of TLR Signaling Pathways by Cell-Permeable Peptides Representing BB Loops of TLRs¹

Vladimir Y. Toshchakov^*, Matthew J. Fenton^2, and Stefanie N. Vogel^3,*

^* Department of Microbiology and Immunology and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland, Baltimore, Baltimore, MD 21201

We designed cell-penetrating peptides comprised of the translocating segment of Drosophila antennapedia homeodomain fused with BB loop sequences of TLR2, TLR4, and TLR1/6. TLR2- and TLR4-BB peptides (BBPs) inhibited NF-B translocation and early IL-1 mRNA expression induced by LPS, and the lipopeptides S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-Ser-Lys₄-OH (P3C) and S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-Cys-Ser-Lys₄-OH (P2C). TLR4- and TLR2-BBPs also strongly inhibited LPS-induced activation of ERK. Only TLR2-BBP significantly inhibited ERK activation induced by P3C, which acts via TLR2/1 heterodimers. BBPs did not inhibit activation of ERK induced by P2C, a TLR2/6 agonist. The TLR2-BBP induced weak activation of p38, but not ERK or cytokine mRNA. The TLR1/6-BBP failed to inhibit NF-B or MAPK activation induced by any agonist. Our results suggest that the receptor BBPs selectively affect different TLR signaling pathways, and that the BB loops of TLR1/6 and TLR2 play distinct roles in formation of receptor heterodimers and recruitment of adaptor proteins.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI47233, AI057490, and AI18797 (to S.N.V.).

² Current address: Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6610 Rockledge Drive, Bethesda, MD 20892.

³ Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, University of Maryland, Baltimore, 660 West Redwood Street, Room 324, Baltimore, MD 21201. E-mail address: svogel{at}som.umaryland.edu

⁴ Abbreviations used in this paper: TIR, Toll/IL-1 resistance; TRAM, TRIF-related adaptor molecule; TIRAP/Mal, TIR domain-containing adaptor molecule; BBP, BB loop peptide; TAK1, TGF--activated kinase 1; IRAK, IL-1R-associated kinase; CP, control peptide; poly(I:C), polyinosinic:polycytidylic acid.

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