Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease.

Abstract

BACKGROUND:

GATA-3 plays a critical role in regulating the expression of the cytokines interleukin (IL)-4, IL-5, and IL-13 from T helper-2 (Th2) cells and therefore is a key mediator of allergic diseases. Corticosteroids are highly effective in suppressing allergic inflammation, but their effects on GATA-3 are unknown. We investigated the effect of the corticosteroid fluticasone propionate on GATA-3 regulation in human T-lymphocytes in vitro and in vivo.

METHODS AND FINDINGS:

In a T lymphocyte cell line (HuT-78) and peripheral blood mononuclear cells stimulated by anti-CD3 and anti-CD28 in vitro we demonstrated that fluticasone inhibits nuclear translocation of GATA-3 and expression of Th2 cytokines via a mechanism independent of nuclear factor-kappaB and is due, in part, to competition between GATA-3 and the ligand-activated glucocorticoid receptor for nuclear transport through the nuclear importer importin-alpha. In addition, fluticasone induces the expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), the endogenous inhibitor of p38 MAPK, which is necessary for GATA-3 nuclear translocation. These inhibitory effects of fluticasone are rapid, potent, and prolonged. We also demonstrated that inhaled fluticasone inhibits GATA-3 nuclear translocation in peripheral blood lymphocytes of patients with asthma in vivo.

CONCLUSIONS:

Corticosteroids have a potent inhibitory effect on GATA-3 via two interacting mechanisms that potently suppress Th2 cytokine expression. This novel mechanism of action of corticosteroids may account for the striking clinical efficacy of corticosteroids in the treatment of allergic diseases.

• Authors: Kittipong Maneechotesuwan, Xin Yao, Kazuhiro Ito, Elen Jazrawi, Omar S Usmani, Ian M Adcock, Peter J Barnes
• Journal: PLoS medicine (PLoS Med) Vol. 6 Issue 5 Pg. e1000076 (May 12 2009) ISSN: 1549-1676 [Electronic] United States
• PMID: 19436703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenal Cortex Hormones
• Androstadienes
• Anti-Allergic Agents
• Cytokines
• GATA3 Transcription Factor
• Receptors, Glucocorticoid
• alpha Karyopherins
• Interleukin-4
• Fluticasone
• Dual Specificity Phosphatase 1

Topics

• Active Transport, Cell Nucleus (drug effects, immunology)
• Administration, Inhalation
• Adrenal Cortex Hormones (immunology, pharmacology, therapeutic use)
• Androstadienes (pharmacology, therapeutic use)
• Anti-Allergic Agents (pharmacology, therapeutic use)
• Asthma (drug therapy)
• Cell Line
• Cytokines (metabolism)
• Dual Specificity Phosphatase 1 (immunology, metabolism)
• Fluticasone
• GATA3 Transcription Factor (metabolism)
• Gene Expression Regulation
• Humans
• Hypersensitivity (drug therapy, immunology, metabolism)
• Interleukin-4 (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Phosphorylation
• Receptors, Glucocorticoid (immunology, metabolism)
• Th2 Cells (drug effects, metabolism)
• alpha Karyopherins (immunology, metabolism)