Assembly of the TLR2/6 Transmembrane Domains Is Essential for Activation and Is a Target for Prevention of Sepsis

Avner Fink, Eliran M. Reuven, Christopher J. Arnusch, Liraz Shmuel-Galia, Niv Antonovsky, Yechiel Shai

פרסום מחקרי: פרסום בכתב עתמאמרביקורת עמיתים

תקציר

TLR2, together with TLR1 and TLR6, is essential for detecting lipopeptides and bacterial cell wall components such as lipoteichoic acid from Gram-positive bacteria. In this study, we report that transmembrane domain (TMD)-derived peptides from TLR2 and TLR6 specifically inhibit TLR2 activation. Secretion of the cytokines TNF-alpha and IL-6 by cultured macrophages (RAW264.7 cell line) was inhibited by these peptides in response to TLR2 activation by lipoteichoic acid (TLR2/6 activator) or palmitoyl (3)-CysSer- Lys(4)-OH (TLR2/1 activator) but not by LPS (TLR4 activator). Extensive biophysical and biochemical assays, combined with GALLEX experiments, show that these peptides heterodimerize with their complementary TMDs on their reciprocal protein. These results suggest that TLR2/6/1 TMD assembly is essential for activating this complex. Importantly, when administered to mice inflicted by TLR2, but not TLR4-driven lethal inflammation, a selected peptide rescued 60% of these septic mice, showing potent in vivo inhibition of TNF-alpha and IL-6 secretion. Furthermore, this peptide also showed high protection in a whole bacteria model. Owing to the importance of TLR2 regulation under a variety of pathological conditions, compounds that can fine-tune this activity are of great importance.
שפה מקוריתאנגלית
עמודים (מ-עד)6410-6422
מספר עמודים13
כתב עתJournal of Immunology
כרך190
מספר גיליון12
מזהי עצם דיגיטלי (DOIs)
סטטוס פרסוםפורסם - 15 יוני 2013

ASJC Scopus subject areas

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