title: Macrophage tolerance induced by stimulation with Toll-like receptor 7/8 ligands.
abstract: The engagement of Toll-like receptors (TLRs) results in resistance to subsequent challenge with respective ligands in macrophages. Studies have shown that stimulation by ligands for TLR2, TLR4, TLR5 and TLR9 induces this state of hypo-responsiveness (homo-tolerance) towards subsequent stimulation with the same ligands. However, whether homo-tolerance is induced by the ligands of TLR7/8 has not been previously determined. We found that ligands for TLR7/8, namely ss-RNA from HIV and an imidazoquinoline compound, R848, induced macrophage tolerance, as judged by the production of the chemokine MIP-1beta. IRAK-1 phosphorylation was also inhibited in the tolerant cells after subsequent stimulation with R848, although no significant differences were observed in the protein levels of TLR7 between tolerant and non-tolerant cells. These results indicate that macrophage tolerance induced by TLR7/8 ligands is regulated at least at the level of IRAK-1 activation.
authors.affiliation: Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Tsukada
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kitazawa
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Fukushima
authors.forename: Shu
authors.initials: S
authors.lastname: Okugawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yanagimoto
authors.forename: Keita
authors.initials: K
authors.lastname: Tatsuno
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagase
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ota
mesh_terms: D000818:Animals; D002460:Cell Line; D054407:Chemokine CCL4; D007108:Immune Tolerance; D008024:Ligands; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D011804:Quinolines / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000187:drug effects / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D054407:Chemokine CCL4; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D011804:Quinolines; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8