title: Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells.
abstract: Prior exposure of dendritic cells (DCs) and monocytes/macrophages to LPS causes unresponsiveness to subsequent LPS stimulation, a phenomenon called endotoxin tolerance (ET). ET impairs antigen presentation of these cells to T cells by down-regulating expression of MHC class II and co-stimulatory molecules such as CD86 and CD40. Some epidemiological studies have shown that endotoxin acts as a protective factor for allergic diseases. Accordingly, LPS has beneficial effects on the onset of airway allergic inflammation in model animals by T(h)1 skewing or induction of regulatory T cells. However, results derived from asthma model animals are controversial, probably due to the difficulty of handling LPS. We previously generated a monoclonal agonistic antibody against Toll-like receptor (TLR) 4, named UT12, which mimics the biological activities of LPS, exhibiting more potent and sustained ET than does LPS. In this study, we took advantage of UT12 to generate prolonged ET to explore the possibility that ET is involved in the inhibitory effects of the TLR4 signals on asthma model mice. Induction of ET by UT12 inhibited the capacity of DCs to expand ovalbumin (OVA)-specific T(h)2 and T(h)17 cells, without inducing T(h)1 cell or regulatory T-cell populations or producing inhibitory cytokines. Accordingly, administration of UT12 before the OVA sensitization significantly suppressed airway allergic inflammation by OVA inhalation. Taken together, these results demonstrate that ET induced by activating TLR4 signals attenuates airway allergic inflammation through direct suppression of the T-cell stimulatory effect of DCs in asthma model mice.
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan.
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Matsushita
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiraishi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.forename: Shuji
authors.initials: S
authors.lastname: Toda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hiroichi
authors.initials: H
authors.lastname: Nagai
authors.forename: Masao
authors.initials: M
authors.lastname: Kimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Inokuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004731:Endotoxins / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D004731:Endotoxins; D051197:Toll-Like Receptor 4; D010047:Ovalbumin