Regulation of Immune Responsiveness In Vivo by Disrupting an Early T-Cell Signaling Event Using a Cell-Permeable Peptide
| Autor: | Wei Duan, Nicholas R. Cam, Constantine D. Tsoukas, Nupura Hirve, John D. Lambris, Michael Croft, David M. Guimond |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
lcsh:Medicine
Cell-Penetrating Peptides Signal transduction medicine.disease_cause Mice Molecular cell biology Membrane Receptor Signaling Lymphocytes lcsh:Science Immune Response Mice Inbred BALB C Multidisciplinary TCR signaling cascade T Cells Allergy and Hypersensitivity Mechanisms of Signal Transduction Signaling cascades Protein-Tyrosine Kinases Flow Cytometry medicine.anatomical_structure Allergic response Cytokines Female Goblet Cells Bronchial Hyperreactivity medicine.symptom Immunologic Receptor Signaling Tyrosine kinase signaling cascade Intracellular Research Article Ovalbumin Immune Cells T cell Immunology Molecular Sequence Data Bronchial mucus Inflammation Biology Immunomodulation Th2 Cells Immune system Eosinophilia medicine Animals Amino Acid Sequence Bronchioles lcsh:R Immunity Pneumonia Immunologic Subspecialties Mice Inbred C57BL Mucus biology.protein lcsh:Q Lymph Nodes Pulmonary Immunology Cytometry |
| Zdroj: | PLoS ONE, Vol 8, Iss 5, p e63645 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0063645 |
| Popis: | The inducible T cell kinase (ITK) regulates type 2 (Th2) cytokines that provide defense against certain parasitic and bacterial infections and are involved in the pathogenesis of lung inflammation such as allergic asthma. Activation of ITK requires the interaction of its SH3 domain with the poly-proline region of its signaling partner, the SH2 domain containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). The specific disruption of the ITK-SH3/SLP-76 poly-proline interaction in vitro by a cell-permeable competitive inhibitor peptide (R9-QQP) interferes with the activation of ITK and the transduction of its cellular functions in T lymphocytes. In the present investigation, we assessed the effects of R9-QQP treatment on the induction of an in vivo immune response as represented by lung inflammation in a murine model of allergic asthma. We found that mice treated with R9-QQP and sensitized and challenged with the surrogate allergen ovalbumin (OVA) display significant inhibition of lung inflammation in a peptide-specific manner. Thus, parameters of the allergic response, such as airway hyper-responsiveness, suppression of inflammatory cell infiltration, reduction of bronchial mucus accumulation, and production of relevant cytokines from draining lymph nodes were significantly suppressed. These findings represent the first demonstration of the biological significance of the interaction between ITK and SLP-76 in the induction of an immune response in a whole animal model and specifically underscore the significance of the ITK-SH3 domain interaction with the poly-proline region of SLP-76 in the development of an inflammatory response. Furthermore, the experimental approach of intracellular peptide-mediated inhibition might be applicable to the study of other important intracellular interactions thus providing a paradigm for dissecting signal transduction pathways. |
| Databáze: | OpenAIRE |
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