Novel anti-inflammatory effects of the inhaled corticosteroid fluticasone propionate during lung myofibroblastic differentiation.
Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-beta-induced expression of alpha-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-kappaB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.
Cazes
E
E
Institut National de la Santé et de la Recherche Médicale Unité 506, Hospital Paul Brousse, Villejuif, France.
Giron-Michel
J
J
Baouz
S
S
Doucet
C
C
Cagnoni
F
F
Oddera
S
S
Körner
M
M
Dasic
G
G
Testi
R
R
Azzarone
B
B
Canonica
G W
GW
D000199:Actins / Q000032:analysis; D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D000068298:Fluticasone; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000502:physiology
D000199:Actins; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D016328:NF-kappa B; D011506:Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D000068298:Fluticasone; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human