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Am J Pathol. 2011 Oct;179(4):2131-41. doi: 10.1016/j.ajpath.2011.06.028. Epub 2011 Aug 22.

Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis.

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1
Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202-5188, USA.

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.

PMID:
21864492
PMCID:
PMC3181363
DOI:
10.1016/j.ajpath.2011.06.028
[Indexed for MEDLINE]
Free PMC Article
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