Journal
JOURNAL OF IMMUNOLOGY
Volume 175, Issue 1, Pages 494-500Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.175.1.494
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Funding
- NIAID NIH HHS [AI-18797, AI-44936] Funding Source: Medline
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TLRs sense pathogens and transmit intracellular signals via the use of specific adapter proteins. We designed a set of blocking peptides (BPs) comprised of the 14 aa that correspond to the sequences of the BB loops of the four known Toll-IL-1 resistance (TIR) domain-containing adapter proteins (i.e., MyD88, TIR domain-containing adapter inducing IFN-beta (TRIF), TRIF-related adapter molecule (TRAM), and TIR-domain containing adapter protein (TIRAP)) linked to the cell-penetrating segment of the antennapedia homeodomain. LPS (TLR4)-mediated gene expression, as well as MAPK and transcription factor activation associated with both MyD88-dependent and -independent signaling pathways, were disrupted by all four BPs (TRAM approximate to MyD88 > TRIF > TIRAP), but not by a control peptide. In contrast, none of the BPs inhibited TLR2-mediated activation of MAPKs. Only the MyD88 BP significantly blocked Pam3Cys-induced IL-1 beta mRNA; however, the inhibitory effect was much less than observed for LPS. Our data suggest that the interactions required for a fully functional TLR4 signaling platform are disrupted by these BPs, and that the adapter BB loops may serve distinct roles in TLR4 and TLR2 signalosome assembly.
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