Alcohol-Induced Interleukin-17 Expression Causes Murine Lung Fibroblast-to-Myofibroblast Transdifferentiation via Thy-1 Down-Regulation.
Alcohol Clin Exp Res
; 43(7): 1427-1438, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-31081931
ABSTRACT
BACKGROUND:
Alcohol exposure induces TGFß1 and renders the lung susceptible to injury and disrepair. We determined that TGFß1 regulates myofibroblast differentiation through the loss of Thy-1 expression and consequent induction of α-SMA. TGFß1 is important for T helper 17 (Th17) differentiation and IL-17 secretion, which in turn participates in tissue repair. We hypothesized that alcohol induces Th17 differentiation via TGFß1 and that IL-17 produced by these cells contributes to the development of profibrotic lung myofibroblasts.METHODS:
Primary lung fibroblasts (PLFs) were treated with alcohol, TGFß1, and IL-17 and then analyzed for Thy-1 expression and cell morphology. Naïve and Th17-polarized CD4+ T cells were exposed to alcohol and assessed for IL-17 expression. CD4+ T cells from alcohol-fed mice were analyzed for Th17 and IL-17 expression. Lungs of control-fed, bleomycin-treated and alcohol-fed, bleomycin-treated mice were analyzed for IL-17 protein expression.RESULTS:
Alcohol-treated PLFs expressed lower levels of Thy-1 than untreated cells. TGFß1 or IL-17 exposure suppressed PLF Thy-1 expression. When administered together, TGFß1 and IL-17 additively down-regulated Thy-1 expression. Exposure of naïve and Th17-polarized CD4+ T cells to alcohol induced the Th17 phenotype and augmented their production of IL-17. CD4+ Th17+ levels are elevated in the peripheral compartment but not in the lungs of alcohol-fed animals. Treatment of the PLFs with IL-17 and alcohol induced α-SMA expression. Induction of α-SMA and myofibroblast morphology by IL-17 occurred selectively in a Thy-1- fibroblast subpopulation. Chronic alcohol ingestion augmented lung-specific IL-17 expression following bleomycin-induced lung injury.CONCLUSIONS:
Alcohol exposure skews T cells toward a Th17 immune response that in turn primes the lung for fibroproliferative disrepair through loss of Thy-1 expression and induction of myofibroblast differentiation. These effects suggest that IL-17 and TGFß1 contribute to fibroproliferative disrepair in the lung and targeting these proteins could limit morbidity and mortality following lung injury in alcoholic individuals.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diferenciación Celular
/
Depresores del Sistema Nervioso Central
/
Antígenos Thy-1
/
Interleucina-17
/
Etanol
/
Miofibroblastos
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Fibroblastos
/
Pulmón
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
Alcohol Clin Exp Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Georgia