Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17

J Immunol. 2011 Nov 1;187(9):4611-20. doi: 10.4049/jimmunol.1100649. Epub 2011 Sep 28.

Abstract

Atopic dermatitis (AD) is a common pruritic inflammatory disease triggered by a defective skin barrier and immunodysregulation. AD has been considered a typical example of a Th2 response associated with allergic disease. In the early phases of the disease, symptoms include IgE hyperproduction, eosinophil accumulation, and mast cell activation; in the chronic phase, a Th1-dominant immune response is also observed at the sites of AD skin lesions. The role of IL-17-producing Th (Th17) cells in AD has not been established. In the current study, we found that pyridone 6 (P6), a pan-JAK inhibitor, delayed the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6 reduced IFN-γ and IL-13, whereas it enhanced IL-17 and IL-22 expression. In vitro, P6 also inhibited both Th1 and Th2 development, whereas it promoted Th17 differentiation from naive T cells when present within a certain range of concentrations. This was probably because P6 strongly inhibited STAT1, STAT5, and STAT6 phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration. Furthermore, IL-22 protects keratinocytes from apoptosis induced by IFN-γ, and administration of IL-17 and IL-22 partially ameliorated skin diseases in NC/Nga mice. These results suggested that the JAK inhibitor P6 is therapeutic for AD by modulating the balance of Th2 and Th17.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Dermatitis, Atopic / drug therapy*
  • Dermatitis, Atopic / immunology
  • Dermatitis, Atopic / pathology*
  • Dermatophagoides farinae / immunology
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / immunology*
  • Growth Inhibitors / administration & dosage
  • Growth Inhibitors / pharmacology
  • Inflammation Mediators / administration & dosage
  • Inflammation Mediators / pharmacology
  • Interleukin-17 / biosynthesis
  • Interleukin-22
  • Interleukins / biosynthesis
  • Janus Kinases / antagonists & inhibitors*
  • Mice
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Th17 Cells / pathology*
  • Th2 Cells / drug effects
  • Th2 Cells / immunology
  • Th2 Cells / pathology*
  • Up-Regulation / drug effects
  • Up-Regulation / immunology*

Substances

  • 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one
  • Benzimidazoles
  • Cytokines
  • Growth Inhibitors
  • Inflammation Mediators
  • Interleukin-17
  • Interleukins
  • Pyridones
  • Janus Kinases