Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation

Antonella Casola, Allyne Henderson, Tianshuang Liu, Roberto Garofalo, Allan R. Brasier

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Regulated on activation, normal T cell expressed, and presumably secreted (RANTES) is a member of the CC chemokine family of proteins implicated in a variety of diseases characterized by lung eosinophilia and inflammation, strongly produced by stimulated airway epithelial cells. Because such cytokines as tumor necrosis factor (TNF)-α and interferon-γ (IFN-γ) have been shown to enhance RANTES induction in airway epithelial cells and RANTES gene expression appears to be differentially regulated depending on the cell type and the stimulus applied, in this study we have elucidated mechanisms that operate to control RANTES induction on exposure to TNF-α and/or IFN-γ. Our results indicate that TNF-α and IFN-γ synergistically induce RANTES protein secretion and mRNA expression. RANTES transcription is activated only after stimulation with TNF-α, but not IFN-γ, which affects RANTES mRNA stabilization. Promoter deletion and mutagenesis experiments indicate that the nuclear factor (NF)-κB site is the most important cis-regulatory element controlling TNF-induced RANTES transcription, although NF-interleukin-6 binding site, cAMP responsive element (CRE), and interferon-stimulated responsive element (ISRE) also play a significant role. TNF-α stimulation induces nuclear translocation of interferon regulatory factor (IRF)-3, which in viral infection binds the RANTES ISRE and is necessary for activation of RANTES transcription. However, TNF-induced IRF-3 translocation does not result in IRF-3 binding to the RANTES ISRE. Although viral infection can activate an ISRE-driven promoter, TNF cannot, indicating that RANTES gene enhancers are controlled in a stimulusspecific fashion. Identification of molecular mechanisms involved in RANTES gene expression is fundamental for developing strategies to modulate lung inflammatory responses.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume283
Issue number6 27-6
StatePublished - Dec 1 2002

Fingerprint

Alveolar Epithelial Cells
Cytokines
T-Lymphocytes
Interferons
Tumor Necrosis Factor-alpha
Interferon Regulatory Factor-3
Virus Diseases
Epithelial Cells
CCAAT-Enhancer-Binding Protein-beta
Gene Expression
CC Chemokines
Messenger RNA
Eosinophilia
Mutagenesis

Keywords

  • Interferon
  • Nuclear factor-κB
  • Regulated on activation, normal T cell expressed, and presumably secreted
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation. / Casola, Antonella; Henderson, Allyne; Liu, Tianshuang; Garofalo, Roberto; Brasier, Allan R.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 283, No. 6 27-6, 01.12.2002.

Research output: Contribution to journalArticle

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