A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice.

Abstract

Interleukin-13 (IL-13) is one of the central mediators for development of airway hyperresponsiveness in asthma. The signal transducer and activation of transcription 6 (STAT6) is one of the major signal transducers activated by IL-13, and a possible involvement of IL-13/STAT6 pathway in the augmented bronchial smooth muscle (BSM) contraction has been suggested. In the present study, the effect of a novel STAT6 inhibitor, AS1517499, on the development of antigen-induced BSM hyperresponsiveness was investigated. In cultured human BSM cells, IL-13 (100 ng/ml) caused a phosphorylation of STAT6 and an up-regulation of RhoA, a monomeric GTPase responsible for Ca2+ sensitization of smooth muscle contraction: both events were inhibited by co-incubation with AS1517499 (100 nM). In BALB/c mice that were actively sensitized and repeatedly challenged with ovalbumin antigen, an increased IL-13 level in bronchoalveolar lavage fluids and a phosphorylation of STAT6 in bronchial tissues were observed after the last antigen challenge. These mice had an augmented BSM contractility to acetylcholine together with an up-regulation of RhoA in bronchial tissues. Intraperitoneal injections of AS1517499 (10 mg/kg) 1 hour before each ovalbumin exposure inhibited both the antigen-induced up-regulation of RhoA and BSM hyperresponsiveness, almost completely. A partial but significant inhibition of antigen-induced production of IL-13 was also found. These findings suggest that the inhibitory effects of STAT6 inhibitory agents, such as AS1517499, both on RhoA and IL-13 up-regulations might be useful for asthma treatment.

• Authors: Yoshihiko Chiba, Michiko Todoroki, Yuichi Nishida, Miki Tanabe, Miwa Misawa
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 41 Issue 5 Pg. 516-24 (Nov 2009) ISSN: 1535-4989 [Electronic] United States
• PMID: 19202006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide
• Anti-Asthmatic Agents
• Antigens
• Interleukin-13
• Pyrimidines
• Recombinant Proteins
• STAT6 Transcription Factor
• STAT6 protein, human
• Stat6 protein, mouse
• RHOA protein, human
• Immunoglobulin E
• Ovalbumin
• RhoA protein, mouse
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein

Topics

• Animals
• Anti-Asthmatic Agents (administration & dosage, pharmacology)
• Antigens
• Asthma (drug therapy, immunology, metabolism, physiopathology)
• Bronchi (drug effects, immunology, metabolism, physiopathology)
• Bronchial Hyperreactivity (immunology, metabolism, physiopathology, prevention & control)
• Bronchoalveolar Lavage Fluid (immunology)
• Bronchoconstriction (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Immunoglobulin E (blood)
• Injections, Intraperitoneal
• Interleukin-13 (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Muscle, Smooth (drug effects, immunology, metabolism, physiopathology)
• Ovalbumin
• Phosphorylation
• Pyrimidines (administration & dosage, pharmacology)
• Recombinant Proteins (metabolism)
• STAT6 Transcription Factor (antagonists & inhibitors, metabolism)
• Time Factors
• rho GTP-Binding Proteins (metabolism)
• rhoA GTP-Binding Protein (metabolism)