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. 2013 Jun 18;8(6):e65921.
doi: 10.1371/journal.pone.0065921. Print 2013.

TLR3, TLR4 and TLRs7-9 Induced Interferons Are Not Impaired in Airway and Blood Cells in Well Controlled Asthma

Annemarie Sykes  1 , Michael R Edwards, Jonathan Macintyre, Ajerico Del Rosario, Vera Gielen, Jennifer Haas, Onn Min Kon, Mark McHale, Sebastian L Johnston
Affiliations

TLR3, TLR4 and TLRs7-9 Induced Interferons Are Not Impaired in Airway and Blood Cells in Well Controlled Asthma

Annemarie Sykes et al. PLoS One. .

Abstract

Defective Rhinovirus induced interferon-β and interferon-λ production has been reported in bronchial epithelial cells from asthmatics but the mechanisms of defective interferon induction in asthma are unknown. Virus infection can induce interferon through Toll like Receptors (TLR)3, TLR7 and TLR8. The role of these TLRs in interferon induction in asthma is unclear. This objective of this study was to measure the type I and III interferon response to TLR in bronchial epithelial cells and peripheral blood cells from atopic asthmatics and non-atopic non-asthmatics. Bronchial epithelial cells and peripheral blood mononuclear cells from atopic asthmatic and non-atopic non-asthmatic subjects were stimulated with agonists to TLR3, TLR4 & TLRs7-9 and type I and III interferon and pro-inflammatory cytokine, interleukin(IL)-6 and IL-8, responses assessed. mRNA expression was analysed by qPCR. Interferon proteins were analysed by ELISA. Pro-inflammatory cytokines were induced by each TLR ligand in both cell types. Ligands to TLR3 and TLR7/8, but not other TLRs, induced interferon-β and interferon-λ in bronchial epithelial cells. The ligand to TLR7/8, but not those to other TLRs, induced only type I interferons in peripheral blood mononuclear cells. No difference was observed in TLR induced interferon or pro-inflammatory cytokine production between asthmatic and non-asthmatic subjects from either cell type. TLR3 and TLR7/8,, stimulation induced interferon in bronchial epithelial cells and peripheral blood mononuclear cells. Interferon induction to TLR agonists was not observed to be different in asthmatics and non-asthmatics.

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Conflict of interest statement

Competing Interests: Author MMH is an employee of AstraZeneca, whose company provided funding towards this study. He has also acted as a consult with Guide Point Global Advisors in non-TLR related subjects. As a Founder of ASLAN Pharmaceuticals Singapore, MMH is a major stock holder. Author SLJ is an author on patents relating to use of IFNs in treatment of exacerbations of airway disease and holds share options in Synairgen, a company developing IFNs for treatment of exacerbations of airway disease. Patent names: Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. UK patent application No. GB 0405634.7, 12 March 2004; Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases. International Patent Application No. PCT/GB05/50031, 12 March 2004; Wark PA, Johnston SL, Holgate ST, Davies DE. The use of Interferon Lambda for the treatment and prevention of virally-induced exacerbation in asthma and chronic pulmonary obstructive disease. UK patent application No. 0518425.4, 9 September 2005; Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-Virus Therapy for Respiratory Diseases. US Patent Application –11/517,763, Patent No.7569216, National Phase of PCT/GB2005/050031, 04 August 2009; Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-beta for Anti-Virus Therapy for Respiratory Diseases. European Patent Number 1734987, 5 May 2010; Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-Virus Therapy for Respiratory Diseases (IFNb therapy) Hong Kong Patent Number 1097181, 31 August 2010; Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-Virus Therapy for Respiratory Diseases (IFNb therapy). Japanese Patent Number 4807526, 26 August 2011; & Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-beta for Anti-Virus Therapy for Respiratory Diseases. New Hong Kong - Divisional Patent Application No.11100187.0, 10 January 2011. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. TLR3 induced type I and III IFN in HBECs.
Figures depict IFN-β protein [A], IFN-β mRNA [B], IFN-λ protein [C], IFN-λ1 mRNA [D] and IFN-λ2/3 mRNA [E] at 8 h following Poly I:C stimulation. Squares represent asthmatics and circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
Figure 2
Figure 2. TLR7 stimulation induced type I and III IFN in HBECs.
Graphs depict IFN-β protein [A], IFN-β mRNA [B], IFN-λ protein [C], IFN-λ1 mRNA [D] and IFN-λ2/3 mRNA [E] at 24 h following stimulation with R848. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
Figure 3
Figure 3. IL-6 induction following TLR stimulation in HBECs.
Graphs depict IL-6 production at 8 h following stimulation with PIC [A] and CpG-B-ODN [B] and at 24 h following R848 [C] and LPS [D]. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
Figure 4
Figure 4. IL-8 induction following TLR stimulation in HBECs.
Graphs depict IL-8 production at 8 h following stimulation with Poly I:C [A], CpG-C-ODN [B], CpG-B-ODN [C] and RNA40 [D] and at 24 h following R848 [E] and LPS [F]. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
Figure 5
Figure 5. TLR7 stimulation induced type I but not type III IFN in PBMCs.
Graphs depict IFN-α protein production 8 h [A], 24 h [B] and 48 h [C] and IFN-β protein at 8 h [D], 24 h [E] and 48 h [F] post R848 stimulation. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
Figure 6
Figure 6. IL-6 induction following TLR stimulation in PBMCs.
Graphs depict IL-6 production at 8 h following stimulation with PIC [A], R848 [D], LPS [G] and LPS [K], 24 h following PIC [B], R848 [E], LPS [H] and LPS [L] and 48 h following PIC [C], R848 [F], LPS [J] and LPS [M]. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
Figure 7
Figure 7. IL-8 induction following TLR stimulation in PBMCs.
Graphs depict IL-8 production at 8 h following stimulation with PIC [A], R848 [B], LPS [C] and RNA40 [D], 24 h following PIC [E], R848 [F], CpG-C-ODN [G], CpG-B-ODN [H], LPS [I] and RNA40 [J] and 48 h following PIC [K]. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.
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