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Cutting Edge: Activation of Toll-Like Receptor 2 Induces a Th2 Immune Response and Promotes Experimental Asthma

Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
The Journal of Immunology (Impact Factor: 5.36). 04/2004; 172(5):2739-43. DOI: 10.4049/jimmunol.172.5.2739
Source: PubMed

ABSTRACT Recognition of microbial components by APCs and their activation through Toll-like receptors (TLR) leads to the induction of adaptive immune responses. In this study, we show that activation of TLR2 by its synthetic ligand Pam3Cys, in contrast to activation of TLR9 by immunostimulatory DNA (ISS-ODN), induces a prominent Th2-biased immune response. Activation of APCs by Pam3Cys resulted in the induction of Th2-associated effector molecules like IL-13, and IL-1beta, GM-CSF and up-regulation of B7RP-1, but low levels of Th1-associated cytokines (IL-12, IFNalpha, IL-18, IL-27). Accordingly, TLR2 ligands aggravated experimental asthma. These data indicate that the type of TLR stimulation during the initial phase of immune activation determines the polarization of the adaptive immune response and may play a role in the initiation of Th2-mediated immune disorders, such as asthma.

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Available from: Hans Haecker, Jan 08, 2014
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    • "Therefore, LPS contaminated ASD may cause aggravation of allergic lung inflammation. Previous reports have demonstrated that co-treatment of TLR2-ligand Pam3Cys and OVA activated an OVA-associated Th2-biased immune response in experimental asthma [23]. Therefore, ultra-pure LPS was used in this study because the LPS made commercially is contaminated with TLR2-ligands. "
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    ABSTRACT: Background A previous study has shown that the aggravation of Asian sand dust (ASD) on ovalbumin (OVA)-induced lung eosinphilia was more severe in lipopolysaccharide (LPS)-rich ASD than in SiO2-rich ASD. Therefore, the effects of different LPS contamination levels in ASD on the aggravation of OVA-induced lung eosinophilia were investigated in the present study. Methods Before beginning the in vivo experiment, we investigated whether the ultra-pure LPS would act only on TLR4 or not using bone marrow-derived macrophages (BMDMs) of wild–type, TLR2-/-, TLR4-/- and MyD88-/- BALB/c mice. ASD collected from the desert was heated to remove toxic organic substances (H-ASD). BALB/c mice were instilled intratracheally with 12 different testing samples prepared with LPS (1 ng and 10 ng), H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), the levels of inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated. Results The LPS exhibited no response to the production of TNF-α and IL-6 in BMDMs from TLR4-/-, but did from TLR2-/-. H-ASD aggravated the LPS-induced neutrophilic lung inflammation. In the presence of OVA, LPS increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 at the levels of 1 ng and 10 ng. In the presence of OVA and H-ASD, LPS induced severe eosinophil infiltration and proliferation of goblet cells in the airways as well as remarkable increases in Th2 cytokines IL-5 and IL-13 in BALF. The mixture containing LPS (1 ng) showed adjuvant activity on OVA-specific IgE and IgG1 production. Conclusions The results suggest that H-ASD with naturally-occurring levels of LPS enhances OVA-induced lung eosinophilia via increases in Th2-mediated cytokines and antigen-specific immunoglobulin. These results indicate that LPS is a strong candidate for being a major aggravating substance in ASD.
    Allergy Asthma and Clinical Immunology 06/2014; 10(1):30. DOI:10.1186/1710-1492-10-30
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    • "Immunization with OVA and a TLR2 agonist (Pam3Cys) induced Th2 immune responses such as the production of antigen-specific IgE in the serum, and IL-13 secretion by splenocytes.27 TLR2 activation promoted airway hyperresponsiveness.27 Double-stranded RNA (dsRNA) increased lung inflammation, airway hyperresponsiveness, and antigen-specific Th2 responses in OVA-sensitized mice through the TLR3-TRIF (Toll/IL-1R domain-containing adaptor-inducing IFN-β) pathway.28 In contrast, intranasal administration of the TLR7 agonist, R848, suppressed experimental asthma by inducing type ? "
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    ABSTRACT: Asthma is a pulmonary chronic inflammatory disease characterized by airway obstruction and hyperresponsiveness. Pattern recognition receptors are known to play a key role in the development of allergic diseases as well as host defenses against microbial infection. Receptor interacting protein 2 (RIP2), a serine/threonine kinase, is an adaptor molecule of NOD1 and NOD2, and genetic variation in this receptor is known to be associated with the severity of allergic asthma in children. In this study, we examined the role of RIP2 in the development of allergic airway inflammation in a mouse model. Airway inflammation was induced in mice through intranasal administration of ovalbumin (OVA) after 2 intraperitoneal immunizations with OVA. Lung inflammation and mucus hypersecretion were examined histologically and total cell infiltration in bronchoalveolar (BAL) fluids was determined. Levels of the Th2-related cytokines, IL-5 and IL-13, in lung extracts were measured by ELISA. Serum antigen-specific IgE and IgG1 levels were also assessed. OVA-induced lung inflammation and mucus hypersecretion were not different between WT and RIP2-deficient mice. The IL-5 and IL-13 levels in the bronchoalveolar (BAL) fluids were also not impaired in RIP2-deficient mice compared to WT mice. Moreover, RIP2 deficiency did not affect serum OVA-specific IgG1 and IgE levels. Our results suggest that RIP2 is not associated with the development of allergic airway inflammation.
    Allergy, asthma & immunology research 03/2014; 6(2):163-8. DOI:10.4168/aair.2014.6.2.163 · 3.08 Impact Factor
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    • "The asthma-like alterations induced in the airway by B. adusta with OVA were much higher than by treatment with B. adusta alone. Previous reports have demonstrated that co-treatment of TLR2-ligand Pam3Cys and OVA activates an OVA-associated Th2-biased immune response in experimental asthma [25]. These results suggest that B. adusta with β-glucan activates an OVA-related Th2-biased immune response through TLR2-dependent signaling pathways. "
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    ABSTRACT: Bjerkandera adusta (B. adusta) is one of the most important etiological fungi associated with chronic cough. However, precise details of the inflammatory response to exposure are not well understood yet. B. adusta was recently identified in Asian sand dust (ASD) aerosol. Therefore, in the present study the exacerbating effects of ASD on B. adusta-induced lung inflammation and B. adusta + ASD on ovalbumin (OVA)-induced murine lung eosinophilia were investigated using experimental mice. In order to prepare testing samples, B. adusta obtained from ASD aerosol was inactivated by formalin and ASD collected from the atmosphere was heated to remove toxic organic substances (H-ASD). CD-1 mice were instilled intratracheally with 12 different samples prepared with various combinations of B. adusta, H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in bronchoalveolar lavage fluid (BALF), and the levels of inflammatory cytokines/chemokines in BALF were investigated. H-ASD aggravated the lung eosinophilia induced by B. adusta alone, which also aggravated the lung eosinophilia induced by OVA. The mixture of OVA, H-ASD, and B. adusta caused serious fibrous thickening of the subepithelial layer, eosinophil infiltration, and proliferation of goblet cells in the airways along with remarkable increases of IL-13, eotaxin, IL-5, and MCP-3 in BALF. The results of the present study demonstrated that B. adusta isolated from ASD aerosol induces allergic lung diseases. H-ASD enhanced allergic reactions caused by OVA or B. adusta. A mixture of B. adusta, H-ASD, and OVA caused the most remarkable exacerbation to the allergic airway inflammation via remarkable increases of pro-inflammatory mediators.
    Allergy Asthma and Clinical Immunology 02/2014; 10(1):10. DOI:10.1186/1710-1492-10-10
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