title: Spred1, a Suppressor of the Ras-ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells.
abstract: Cytokines from group 2 innate lymphoid cells (ILC2s) have been implicated in acute allergic responses, such as papain-induced lung inflammation. However, the means of homeostatic regulation of ILC2s have not been established. In this study, we demonstrated that Spred1, a negative regulator of the Ras-ERK pathway, plays an important role in the proliferation and apoptosis of ILC2s and in cytokine secretion from ILC2s. Intranasal administration of papain stimulated IL-5 and IL-13 production in the lung, which was enhanced when Spred1 was deleted. In vitro, Spred1(-/-) ILC2s proliferated faster than wild type ILC2s did and produced higher levels of cytokines in response to IL-33. On the contrary, a MEK inhibitor suppressed ILC2 proliferation and cytokine production. Spred1 deficiency resulted in stabilization of GATA3, which has been shown to play essential roles in the maintenance and cytokine production of ILC2. These data suggest that Spred1 negatively regulates ILC2 development and functions through the suppression of the Ras-ERK pathway.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan; and.
authors.forename: Mayu
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan; and.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan; and.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Precursory Research for Embryonic Science and Technology, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shichita
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan; and yoshimura@a6.keio.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000096:biosynthesis; D007378:Interleukins; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010206:Papain / Q000009:adverse effects*; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D012097:Repressor Proteins; C433763:Spred1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D010206:Papain; D015689:Oncogene Protein p21(ras)