TLR2 agonist ameliorates established allergic airway inflammation by promoting Th1 response and not via regulatory T cells.
TLRs are primary sensors of both innate and adaptive immune systems, where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 is a TLR2 agonist capable of modulating Th1 and Th2 responses. This study examines the therapeutic effect of Pam3CSK4 in established airway inflammation in a murine model of asthma. In mice previously sensitized and challenged with OVA, Pam3CSK4 given i.p. markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFN-gamma, IL-12, and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGF-beta, but was critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. Our results provide direct evidence that Pam3CSK4 could represent a novel therapeutic agent in allergic airways disease.
Patel
Manish
M
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom.
Xu
Damo
D
Kewin
Pete
P
Choo-Kang
Brian
B
McSharry
Charles
C
Thomson
Neil C
NC
Liew
Foo Y
FY
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology; D008074:Lipoproteins / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology; D011971:Receptors, Immunologic / Q000819:agonists* / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta / Q000502:physiology
D008074:Lipoproteins; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin