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

Ryusuke Nakagawa, Hideyuki Yoshida, Mayako Asakawa, Taiga Tamiya, Naoko Inoue, Rimpei Morita, Hiromasa Inoue, Atsuhito Nakao, Akihiko Yoshimura

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4611-4620
Number of pages10
JournalJournal of Immunology
Volume187
Issue number9
DOIs
Publication statusPublished - 2011 Nov 1

Fingerprint

Atopic Dermatitis
Inflammation
Skin
Interleukin-17
Skin Diseases
Phosphorylation
Th17 Cells
Interleukin-13
Keratinocytes
Eosinophils
Mast Cells
Immunoglobulin E
2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one
Apoptosis
T-Lymphocytes
interleukin-22

ASJC Scopus subject areas

  • Immunology

Cite this

Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. / Nakagawa, Ryusuke; Yoshida, Hideyuki; Asakawa, Mayako; Tamiya, Taiga; Inoue, Naoko; Morita, Rimpei; Inoue, Hiromasa; Nakao, Atsuhito; Yoshimura, Akihiko.

In: Journal of Immunology, Vol. 187, No. 9, 01.11.2011, p. 4611-4620.

Research output: Contribution to journalArticle

Nakagawa, Ryusuke ; Yoshida, Hideyuki ; Asakawa, Mayako ; Tamiya, Taiga ; Inoue, Naoko ; Morita, Rimpei ; Inoue, Hiromasa ; Nakao, Atsuhito ; Yoshimura, Akihiko. / Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. In: Journal of Immunology. 2011 ; Vol. 187, No. 9. pp. 4611-4620.
@article{350bd4a1c3a943959dea75feb52dc555,
title = "Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17",
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.",
author = "Ryusuke Nakagawa and Hideyuki Yoshida and Mayako Asakawa and Taiga Tamiya and Naoko Inoue and Rimpei Morita and Hiromasa Inoue and Atsuhito Nakao and Akihiko Yoshimura",
year = "2011",
month = "11",
day = "1",
doi = "10.4049/jimmunol.1100649",
language = "English",
volume = "187",
pages = "4611--4620",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "9",

}

TY - JOUR

T1 - Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17

AU - Nakagawa, Ryusuke

AU - Yoshida, Hideyuki

AU - Asakawa, Mayako

AU - Tamiya, Taiga

AU - Inoue, Naoko

AU - Morita, Rimpei

AU - Inoue, Hiromasa

AU - Nakao, Atsuhito

AU - Yoshimura, Akihiko

PY - 2011/11/1

Y1 - 2011/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80555126112&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80555126112&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1100649

DO - 10.4049/jimmunol.1100649

M3 - Article

VL - 187

SP - 4611

EP - 4620

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 9

ER -