P38 MAPK and glucocorticoid receptor crosstalk in bronchial epithelial cells.
J Mol Med (Berl)
; 98(3): 361-374, 2020 03.
Article
en En
| MEDLINE
| ID: mdl-31974640
ABSTRACT
p38 MAPK inhibition may have additive and synergistic anti-inflammatory effects when used with corticosteroids. We investigated crosstalk between p38 MAPK inhibitors and corticosteroids in bronchial epithelial cells to investigate synergistic effects on cytokine production and the molecular mechanisms involved. Effects of the p38 MAPK inhibitor BIRB-796 and dexamethasone alone and in combination on LPS, polyIC or TNFα -induced IL-6, CXCL8 and RANTES were assessed in 16HBEs (human epithelial cell line) and on TNFα-induced IL-6 and CXCL8 in primary human epithelial cells from asthma patients and healthy controls. 16HBEs were used to assess effects of BIRB-796 alone and in combination with dexamethasone on glucocorticoid receptor (GR) activity by reporter gene assay, expression of GR target genes and nuclear localisation using Western blot. The effects of BIRB-796 on TNFα stimulated phosphorylation of p38 MAPK and GR at serine (S) 226 by Western blot. Epithelial levels of phosphorylated p38 MAPK and GR S226 were determined by immunohistochemistry in bronchial biopsies from asthma patients and healthy controls. BIRB-796 in combination with dexamethasone increased inhibition of cytokine production in a synergistic manner. Combination treatment significantly increased GR nuclear localisation compared to dexamethasone alone. BIRB-796 inhibited TNFα-induced p38 MAPK and GR S226 phosphorylation. Phosphorylated GR S226 and p38 MAPK levels were increased in bronchial epithelium of more severe asthma patients. Molecular crosstalk exists between p38 MAPK activation and GR function in human bronchial epithelial cells, which alters GR activity. Combining a p38 MAPK inhibitor and a corticosteroid may demonstrate therapeutic potential in severe asthma. KEY MESSAGES ⢠Combination of corticosteroid and p38 inhibitor in human bronchial epithelial cells ⢠Combination increased cytokine inhibition synergistically and nuclear GR ⢠p38 MAPK inhibition reduced TNFα-induced phosphorylation of GR at S226 but not S211 ⢠Phosphorylated GRS226 and p38 is increased in bronchial epithelium in severe asthma ⢠Combining a p38 inhibitor and a corticosteroid may be effective in asthma treatment.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirazoles
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Dexametasona
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Receptores de Glucocorticoides
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Proteínas Quinasas p38 Activadas por Mitógenos
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Inhibidores de Proteínas Quinasas
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Células Epiteliales
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Glucocorticoides
/
Naftalenos
Límite:
Humans
Idioma:
En
Revista:
J Mol Med (Berl)
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido