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Pulmonary Suppressor of Cytokine Signaling-1 Induced by IL-13 Regulates Allergic Asthma Phenotype

¹ Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, and ³ Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; ² Discipline of Pharmacology, and the Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia; ⁴ Laboratory for Signal Network, RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan; ⁵ Department of Internal Medicine 1, Kurume University School of Medicine, Kurume, Japan; ⁶ Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan; and ⁷ MRC Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Hiromasa Inoue, M.D., Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: inoue{at}kokyu.med.kyushu-u.ac.jp

Rationale: Th2 cytokines play an important role in allergic diseases. These cytokines activate signal transduction pathways, including Janus kinase/signal transducer and activator of transcription (STAT) signaling. Although the suppressor of cytokine signaling (SOCS) family protein, a negative regulator of the Janus kinase/STAT signaling pathway, contributes to helper T cell differentiation during immune responses, the role of SOCS proteins within the structural cells of a target organ has not been clarified in allergy.

Objectives: To study the local function of SOCS in the development of asthma.

Methods: We used mouse models of IL-13– and ovalbumin (OVA)–induced allergic airway disease. Airway smooth muscle cells were cultured from patients with asthma.

Measurements and Main Results: The administration of IL-13 induced not only airway responses but also SOCS1 expression at the local inflammatory site. The up-regulated SOCS1 markedly suppressed IL-13–dependent STAT6 activation and eotaxin expression and subsequently down-regulated IL-13–induced airway inflammatory responses. The inactivation of SOCS1 induced airway hyperresponsiveness after IL-13 treatment even in hyporesponsive C57BL/6 background mice. In an OVA-induced model of allergic airway disease, allergen exposure up-regulated local SOCS1 expression, and the induction of SOCS1 in the airways attenuated allergen-induced airway responses. Inactivation of IL-13 inhibited SOCS1 induction in a model of allergic airway disease. Interestingly, airway smooth muscle cells from individuals with asthma had impaired up-regulation of SOCS1 after IL-13 stimulation.

Conclusions: SOCS1 induction by IL-13 in airway structural cells is critical to negatively control allergic airway disease.

Key Words: allergy • Th2 cytokine • signal transducer and activator of transcription-6 • repressor molecule

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Suppressor of cytokine signaling (SOCS) proteins are known to play a critical role in helper T cell differentiation in allergic diseases; however, their local function in airway structural cells is less well defined. What This Study Adds to the Field SOCS1 induction in the airways negatively controls allergic responses in mice, suggesting that aberrant action of SOCS1 may contribute to the pathophysiology of asthma.