Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma.
Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathways play a critical role in allergic asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on asthmatic responses in a mouse model and investigated the mechanism for its biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6 treatment during the challenge phase suppressed eosinophilia in bronchoalveolar lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To improve the efficacy of the JAK inhibitor, P6 was encapsulated in polylactic-coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13 levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge phase treatment with P6-PLGA were similar to those after a sham treatment, the eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum OVA-specific IgE were decreased, while IL-17-producing T cells were increased by P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6 strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6 activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by inhibiting Th2 inflammation and that application of PLGA nanoparticles improves the therapeutic potency of P6.
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Yuko
Y
Matsunaga
Hiromasa
H
Inoue
Satoru
S
Fukuyama
Hideyuki
H
Yoshida
Atsushi
A
Moriwaki
Takafumi
T
Matsumoto
Koichiro
K
Matsumoto
Yukari
Y
Asai
Masato
M
Kubo
Akihiko
A
Yoshimura
Yoichi
Y
Nakanishi
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002214:Capsules; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004802:Eosinophilia / Q000188:drug therapy / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D019344:Lactic Acid / Q000737:chemistry; D008168:Lung / Q000276:immunology; D051379:Mice; D009088:Mucoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D010047:Ovalbumin / Q000276:immunology; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011728:Pyridones / Q000008:administration & dosage / Q000627:therapeutic use*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology
C524063:2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one; D001562:Benzimidazoles; D002214:Capsules; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D018793:Interleukin-13; D009088:Mucoproteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin; D053612:Janus Kinases