Experimental dermatology, 2011-01, Vol.20 (1), p.41-47
2011
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Details
- Autor(en) / Beteiligte
- Titel
- Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases
- Ist Teil von
- Experimental dermatology, 2011-01, Vol.20 (1), p.41-47
- Ort / Verlag
- Oxford, UK: Blackwell Publishing Ltd
- Erscheinungsjahr
- 2011
- Quelle
- Wiley Blackwell Single Titles
- Beschreibungen/Notizen
- : T‐cell‐mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL‐2‐inducible tyrosine kinase (Itk), an enzyme acting downstream of the T‐cell receptor (TCR), in T‐cell‐dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions. Systemic administration of a novel small molecule Itk inhibitor, Compound 44, created by chemical optimization of an initial high‐throughput screening hit, inhibited Itk’s activity with an IC50 in the nanomolar range. Compound 44 substantially reduced proinflammatory immune responses in vitro and in vivo after systemic administration in two acute CHS models. In addition, our data reveal that human Itk, comparable to its murine homologue, is expressed mainly in T cells and is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis. Finally, silencing of Itk by RNA interference in primary human T cells efficiently blocks TCR–induced lymphokine secretion. In conclusion, Itk represents an interesting new target for the therapy of T‐cell‐mediated inflammatory skin diseases.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0906-6705eISSN: 1600-0625DOI: 10.1111/j.1600-0625.2010.01198.xTitel-ID: cdi_proquest_miscellaneous_818642604
- Format
- –
- Schlagworte
- Allergic diseases, Animals, atopic dermatitis, Base Sequence, Biological and medical sciences, contact allergy, contact dermatitis, Dermatitis - drug therapy, Dermatitis - enzymology, Dermatitis - immunology, Dermatitis, Allergic Contact - drug therapy, Dermatitis, Allergic Contact - enzymology, Dermatitis, Allergic Contact - immunology, Dermatitis, Atopic - drug therapy, Dermatitis, Atopic - enzymology, Dermatitis, Atopic - immunology, Dermatology, Dinitrochlorobenzene - immunology, Dinitrochlorobenzene - toxicity, Disease Models, Animal, drug discovery, Drug Evaluation, Preclinical, Female, Gene Expression Profiling, Humans, immunology, Immunopathology, In Vitro Techniques, inflammation, kinases, Lymphoid Tissue - enzymology, Lymphoid Tissue - immunology, Medical sciences, Mice, Mice, Knockout, pharmacology, Protein Kinase Inhibitors - pharmacology, Protein-Tyrosine Kinases - antagonists & inhibitors, Protein-Tyrosine Kinases - deficiency, Protein-Tyrosine Kinases - genetics, psoriasis, Psoriasis - drug therapy, Psoriasis - enzymology, Psoriasis - immunology, Psoriasis. Parapsoriasis. Lichen, Recombinant Fusion Proteins - antagonists & inhibitors, Recombinant Fusion Proteins - genetics, RNA Interference, RNA, Messenger - genetics, RNA, Messenger - metabolism, RNA, Small Interfering - genetics, Skin allergic diseases. Stinging insect allergies, T-Lymphocytes - drug effects, T-Lymphocytes - enzymology, T-Lymphocytes - immunology, Up-Regulation