title: Roles of lipoxin A4 receptor activation and anti-interleukin-1β antibody on the toll-like receptor 2/mycloid differentiation factor 88/nuclear factor-κB pathway in airway inflammation induced by ovalbumin.
abstract: Previous studies investigating the role of toll-like receptors (TLRs) in asthma have been inconclusive. It has remained elusive whether the toll-like receptors (TLR2)/mycloid differentiation factor 88 (MyD88)/nuclear factor (NF)-κB signaling pathway is involved in lipoxin A4 (LXA4)-induced protection against asthma. Therefore, the present study investigated whether ovalbumin (OVA)-induced airway inflammation is mediated by upregulation of the TLR2/MyD88/NF-κB signaling pathway, and whether it proceeds via the inhibition of the activation of the LXA4 receptor and anti-interleukin (IL)-1β antibodies. Mice with airway inflammation induced by OVA administration were treated with or without a LXA4 receptor agonist, BML-111 and anti-IL-1β antibody. Serum levels of IL-1β, IL-4, IL-8 and interferon-γ (IFN-γ) were assessed, and levels of IL-1β, IL-4, IL-8 and OVA-immunoglobulin (Ig)E, as well as leukocyte counts in the bronchoalveolar lavage fluid (BALF) were measured. Pathological features and expression of TLR2, MyD88 and NF-κB in the lungs were analyzed. Expression of TLR2 and MyD88, and activation of NF-κB in leukocytes as well as levels of IL-4, IL-6 and IL-8 released from leukocytes exposed to IL-1β were assessed. OVA treatment increased the levels of IL-1β, IL-4 and IL-8 in the serum and BLAF, the number of leukocytes and the levels of OVA-IgE in the BALF, the expression of TLR2 and MyD88, and the activation of NF-κB in the lung. These increments induced by OVA were inhibited by treatment with BML-111 and anti-IL-1β antibodies. Treatment of the leukocytes with BML-111 or TLR2 antibody, or MyD88 or NF-κB inhibitor, all blocked the IL-1β-triggered production of IL-4, IL-6 and IL-8 and activation of NF-κB. Treatment of the leukocytes with BML-111 or TLR2 antibody suppressed IL-1β-induced TLR2 and MyD88 expression. The present study therefore suggested that OVA-induced airway inflammation is mediated by the TLR2/MyD88/NF-κB pathway. IL-1β has a pivotal role in the airway inflammation and upregulation of the TLR2/MyD88/NF-κB pathway induced by OVA. BML-111 and anti-IL-1β antibody restrains the OVA-induced airway inflammation via downregulation of the TLR2/MyD88/NF-κB pathway.
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Chen
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D044045:Lipoxins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D010047:Ovalbumin; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
chemical_list: C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D006538:Heptanoic Acids; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D044045:Lipoxins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D044042:Receptors, Formyl Peptide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; D015847:Interleukin-4; D010047:Ovalbumin