title: Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation.
abstract: Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.
authors.affiliation: 1] Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan [2] Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan [3] Laboratory for Immune Cell System, RCAI, RIKEN Research Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehiro-cho, Yokohama 230-0045, Japan [4].
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kabata
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Moro
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Jun
authors.initials: J
authors.lastname: Miyata
authors.forename: Katsunori
authors.initials: K
authors.lastname: Masaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004361:Drug Tolerance; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D010868:Pimozide / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000305:Adrenal Cortex Hormones; D057134:Antibodies, Neutralizing; C494812:Bcl2l1 protein, mouse; D016207:Cytokines; D018492:Dopamine Antagonists; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D010868:Pimozide; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse