title: BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis.
abstract: Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis.
  
  
  
  Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo.
  
  
  
  Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids.
  
  
  
  Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma.
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Banuelos
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shin
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Bochner
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Morales-Nebreda
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: G R S
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: Departments of Pathology and Immunology/Microbiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Human Tissue Resource Center, The University of Chicago, Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Human Tissue Resource Center, The University of Chicago, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xin
authors.affiliation: Department of Pharmacology and Human Tissue Resource Center, The University of Chicago, Chicago, IL, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Lingen
authors.affiliation: Basic Medical Sciences, Tsinghua University, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Dong
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Schleimer
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: N Z
authors.initials: NZ
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D019254:Genes, bcl-2; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D005938:Glucocorticoids
keywords: T cells; Th17 cells; apoptosis; asthma; glucocorticoids