Immunomodulatory effects of viral TLR ligands on experimental asthma depend on the additive effects of IL-12 and IL-10.

Abstract

Based on epidemiological data, the hygiene hypothesis associates poor hygienic living conditions during childhood with a lower risk for the development of allergic diseases such as bronchial asthma. The role of viral infections, and especially of viral TLR ligands, within this context remains to be clarified. Viral TLR ligands involve dsRNA and ssRNA which are recognized by TLR-3 or TLR-7, respectively. In this study, we evaluated the impact of TLR-3 or TLR-7 activation on experimental asthma in mice. Systemic application of the synthetic TLR-3 or TLR-7 ligands polycytidylic-polyinosinic acid (p(I:C)) or R-848, respectively, during the sensitization phase prevented the production of OVA-specific IgE and IgG1 Abs and subsequently abolished all features of experimental asthma including airway hyperresponsiveness and allergic airway inflammation. Furthermore, administration of p(I:C) or R-848 to animals with already established primary allergic responses revealed a markedly reduced secondary response following allergen aerosol rechallenges. In contrast to wild-type animals, application of p(I:C) or R-848 to IL-12p35(-/-) mice had no effect on airway inflammation, goblet cell hyperplasia, and airway hyperresponsiveness. However, in the absence of IL-12, the numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids were still significantly reduced. These partial effects could also be abolished by neutralizing anti-IL-10 Abs in IL-12p35(-/-) mice. These data indicate that TLR-3 or TLR-7 activation by viral TLR ligands has both preventive as well as suppressive effects on experimental asthma which is mediated by the additive effects of IL-12 and IL-10.

• Authors: Serdar Sel, Michael Wegmann, Sarper Sel, Stefan Bauer, Holger Garn, Gottfried Alber, Harald Renz
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 12 Pg. 7805-13 (Jun 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17548618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Antiviral Agents
• Cytokines
• Imidazoles
• Immunoglobulin G
• Interleukin-12 Subunit p35
• Ligands
• Membrane Glycoproteins
• TLR3 protein, mouse
• Tlr7 protein, mouse
• Toll-Like Receptor 3
• Toll-Like Receptor 7
• Interleukin-10
• Interleukin-12
• Immunoglobulin E
• Ovalbumin
• Poly I-C
• resiquimod

Topics

• Animals
• Antibodies (pharmacology)
• Antiviral Agents (administration & dosage)
• Asthma (immunology, pathology, prevention & control)
• Bronchial Hyperreactivity (immunology, pathology, prevention & control)
• Bronchoalveolar Lavage Fluid (immunology)
• Cytokines (metabolism)
• Female
• Imidazoles (administration & dosage)
• Immunoglobulin E (metabolism)
• Immunoglobulin G (metabolism)
• Immunosuppression Therapy
• Interleukin-10 (antagonists & inhibitors, metabolism)
• Interleukin-12 (antagonists & inhibitors, genetics, metabolism)
• Interleukin-12 Subunit p35 (genetics)
• Ligands
• Membrane Glycoproteins (agonists)
• Mice
• Mice, Inbred BALB C
• Mice, Mutant Strains
• Ovalbumin (immunology)
• Poly I-C (administration & dosage)
• Toll-Like Receptor 3 (agonists)
• Toll-Like Receptor 7 (agonists)