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: 4.92). 04/2004; 172(5):2739-43. DOI: 10.4049/jimmunol.172.5.2739
Source: PubMed


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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    • "At the same time, TLRs contribute to commence adaptive response by favoring the activation of DCs and other APCs, T-cell priming, selective recruitment/differentiation/ regulation of helper (Th) cells, development/modulation of regulatory and effector T cells, as well as regulation of NK and B cells (Kubo et al., 2004; Pasare and Medzhitov, 2005; Meyer- Bahlburg et al., 2007; Kumar et al., 2008). From epidemiologic studies, reduced early-life exposure to infections contributes to a selective Th1/Th2 switch towards Th2 phenotype (leading to allergic symptoms), implying that infections induce Th1- biased immuno-responsiveness, which in turn protects host from diseases fueled by Th2-biased immune regulation (Eisenbarth et al., 2002; Dabbagh and Lewis, 2003; Redecke et al., 2004). Improved/excessive hygiene, vaccination and improper use of antibiotics (representative of industrialized countries) might favor this imbalance. "
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    ABSTRACT: The Toll-like Receptor (TLR) family ensures prompt response towards pathogens, protecting the host against infections, and guarantees a realistic balance between protective and detrimental activities. Multiple regulating mechanisms characterize TLR activity that is not limited to innate and adaptive antimicrobial immune responses, as observed in the inflammatory (either infective, allergic or autoimmune) responses associated with tissue remodeling. Following the insult and the arise of inflammatory response, tissue remodeling takes place and might develop in fibrosis, depending on microenvironment as a result of imbalanced fibroblasts (FBs) and myofibroblasts (myoFBs) activation/survival. The process is driven by an epithelial-fibroblast-immune cell cross-talk. While the main FB function is the matrix metabolism for tissue homeostasis or repair, the myoFB differentiation represents a crucial step in attempting repair of injury. FBs/myoFBs provide more than structural support at site of injury, synthesizing and/or reacting to different cytokines, growth factors, neuromediators and soluble/lipid mediators. TLR-bearing FBs/myoFBs might contribute at the innate immune level, providing a second line of protection/defense as well as being a target/effector cell of tissue remodeling. TLRs might also interfere with acute inflammation as well as with established fibrosis, triggering structural/functional changes in agreement with the genetic background, the site of lesion, the entity of associated infection, the poor blood circulation or the pharmacological treatments, all together strictly influencing tissue repair/remodeling process. This review will focus on the recent findings on TLRs at launch and long-lasting tissue remodeling process, that strongly suggest TLRs as optional targets for future therapies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 08/2015; DOI:10.1002/jcp.25124 · 3.84 Impact Factor
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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 · 2.03 Impact Factor
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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 · 2.43 Impact Factor
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