title: Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis.
abstract: Signal transducer and activator of transcription 3 (Stat3) is a potent transcription factor with diverse biological functions. Overexpression of constitutively active form Stat3C in lung alveolar type II (AT II) epithelial cells in CCSP-rtTA/(tetO)(7)-CMV-Stat3C bitransgenic mice induces chronic inflammation and lung bronchioalveolar adenocarcinoma. In the present study, the population of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) was significantly increased in lung and blood of doxycycline-treated bitransgenic mice, but CD4(+) and CD8(+) T cells were decreased. In bronchioalveolar lavage fluid and plasma of doxycycline-treated bitransgenic mice, concentrations of MDSC-stimulating cytokines IL-1β, IL-6, IL-10, IL-13, INF-γ, TNF-α, and GM-CSF were significantly increased, which stimulated alveolar monocytes/macrophages to CD11b(+)Gr-1(+) cell conversion in vitro. Phosphorylation of proto-oncogenic intracellular signaling molecules Stat3, Erk1/2, and P38 was significantly increased in CD11b(+)Gr-1(+) cells from lung and blood of doxycycline-treated bitransgenic mice. CD11b(+)Gr-1(+) cells from lung of doxycycline-treated bitransgenic mice strongly inhibited proliferation and function of wild-type CD4(+) T cells in vitro. These findings support the concept that persistent activation of Stat3 induces inflammation during lung cancer by promoting MDSC-mediated immune suppression.
authors.affiliation: Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202-5188, USA.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Qu
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D018845:CD11 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000473:pathology*; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008175:Lung Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000950:Antigens, Ly; D018845:CD11 Antigens; D016207:Cytokines; C480309:Ly6G antigen, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse