NDLI: Assembly of the TLR2/6 transmembrane domains is essential for activation and is a target for prevention of sepsis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Shai, Yechiel Shmuel-Galia, Liraz Arnusch, Christopher J. Antonovsky, Niv Fink, Avner Reuven, Eliran M.
Description	Country affiliation: Israel Author Affiliation: Fink A ( Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.)
Abstract	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- 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)-Cys-Ser-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- 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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	12
Volume Number	190
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-06-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Sepsis Metabolism Signal Transduction Immunology Toll-like Receptor 2 Toll-like Receptor 6 Animals Cell Line Fluorescence Resonance Energy Transfer Immunoprecipitation Macrophages Mice Mice, Inbred C57bl Peptides Chemistry Protein Structure, Secondary Protein Structure, Tertiary Physiology Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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