Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases

Exp Dermatol. 2011 Jan;20(1):41-7. doi: 10.1111/j.1600-0625.2010.01198.x.


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.

MeSH terms

  • Animals
  • Base Sequence
  • 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
  • Dinitrochlorobenzene / immunology
  • Dinitrochlorobenzene / toxicity
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Gene Expression Profiling
  • Humans
  • In Vitro Techniques
  • Lymphoid Tissue / enzymology
  • Lymphoid Tissue / immunology
  • Mice
  • Mice, Knockout
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Psoriasis / drug therapy
  • Psoriasis / enzymology
  • Psoriasis / immunology
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / genetics
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • Up-Regulation


  • Dinitrochlorobenzene
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase