IL-13-induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells

Clin Exp Allergy. 2011 Dec;41(12):1747-56. doi: 10.1111/j.1365-2222.2011.03852.x. Epub 2011 Sep 20.

Abstract

Background: Glucocorticosteroids (GCS) are used to treat bronchial asthma, but are not uniformly effective, especially in severe asthma. IL-13 is a T helper type 2 cytokine implicated in the pathogenesis of asthma, and IL-13 induces mucus production and goblet cell hyperplasia in airway epithelial cells. The effect of GCS on IL-13-induced mucin production is not well characterized.

Objective: The aim of this study was to evaluate the effect of dexamethasone (Dex), a potent synthetic GCS, on IL-13-induced MUC5AC mucin expression and goblet cell proliferation in differentiated normal human bronchial epithelial cells (NHBECs).

Methods: NHBECs were cultured for 14 days at an air-liquid interface with IL-13, with or without Dex. MUC5AC protein secretion and mRNA expression was determined using ELISA and quantitative real-time PCR. IL-8 production was assayed using ELISA. Histochemical analysis was performed using H&E and periodic acid-Schiff stain, and MUC5AC immunostaining.

Results: Although Dex dose dependently inhibited IL-8 release induced by 5 ng/mL IL-13, Dex 0.001-1 μg/mL had no effect on IL-13 induced MUC5AC protein secretion or mRNA expression. Dex paradoxically increased MUC5AC induced by IL-13 at 0.5 and 1 ng/mL, but had no effect alone or with IL-13 at 0.1 ng/mL. Dex 0.001-1 μg/mL did not inhibit the differentiation of cells into goblet cells and MUC5AC-positive cells induced by IL-13.

Conclusion and clinical relevance: Dex at therapeutic concentrations did not inhibit the effects of IL-13 on goblet cell differentiation, characteristic of severe asthma. Paradoxically, MUC5AC production was increased with lower dose IL-13 exposure. This may lead to airway mucus obstruction commonly seen in life-threatening asthma.

MeSH terms

  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Dexamethasone / pharmacology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Goblet Cells / cytology*
  • Goblet Cells / drug effects*
  • Humans
  • Interleukin-13 / pharmacology*
  • Interleukin-8 / biosynthesis
  • Mucin 5AC / biosynthesis*
  • Mucin 5AC / genetics
  • RNA, Messenger / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • Interleukin-13
  • Interleukin-8
  • Mucin 5AC
  • RNA, Messenger
  • Dexamethasone