Gamma-secretase inhibitor reduces allergic pulmonary inflammation by modulating Th1 and Th2 responses.

Abstract

RATIONALE:

Gamma-secretase inhibitor (GSI) has been used to effectively block Notch signaling, which is implicated in the differentiation and functional regulation of T helper (Th) effector cells. In asthma, a subset of CD4(+) T cells is believed to initiate and perpetuate the disease.

OBJECTIVES:

The aim of this study was to evaluate the therapeutic potential of GSI against allergic asthma.

METHODS:

GSI was administered to an ovalbumin-sensitized mouse via an intranasal route at the time of ovalbumin challenge.

MEASUREMENTS AND MAIN RESULTS:

The administration of GSI inhibits asthma phenotypes, including eosinophilic airway inflammation, goblet cell metaplasia, methacholine-induced airway hyperresponsiveness, and serum IgE production. GSI treatment of bronchoalveolar lavage cells stimulated via TCR or non-TCR pathways led to a decrease in Th2 cytokine production with a concomitant increase in Th1 cytokine secretion. Expression of Hes-1, a target of Notch signaling, was down-regulated in conjunction with a reduction of Notch intracellular domain and GATA-3 levels after GSI treatment of bronchoalveolar lavage cells. GSI treatment resulted in an inhibition of NF-kappaB activation, and combined treatment with GSI and an NF-kappaB inhibitor augmented IFN-gamma production in a synergistic manner.

CONCLUSIONS:

These data suggest that GSI directly regulates Th1 and Th2 responses in allergic pulmonary inflammation through a Notch signaling-dependent pathway and that GSI is of high therapeutic value for treating asthma by inhibiting airway inflammatory responses.

• Authors: Jin Hyun Kang, Byung Soo Kim, Tae Gi Uhm, Shin-Hwa Lee, Gap Ryol Lee, Choon-Sik Park, Il Yup Chung
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 179 Issue 10 Pg. 875-82 (May 15 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 19234107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• GATA3 Transcription Factor
• NF-kappa B
• Oligopeptides
• Receptors, Notch
• benzyloxycarbonyl-leucyl-leucyl-norleucinal
• Ovalbumin
• Amyloid Precursor Protein Secretases

Topics

• Administration, Intranasal
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, immunology)
• Animals
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Cytokines (biosynthesis, immunology)
• Drug Synergism
• Eosinophilia (drug therapy, enzymology, immunology)
• GATA3 Transcription Factor (biosynthesis)
• Male
• Mice
• Mice, Inbred BALB C
• NF-kappa B (antagonists & inhibitors, immunology)
• Oligopeptides (pharmacology)
• Ovalbumin (administration & dosage, immunology)
• Pneumonia (drug therapy, enzymology, immunology)
• Receptors, Notch (metabolism)
• Respiratory Hypersensitivity (drug therapy, enzymology, immunology)
• Signal Transduction (drug effects)
• Th1 Cells (drug effects, immunology)
• Th2 Cells (drug effects, immunology)