CD4+CD25+Foxp3+ regulatory T cells depletion may attenuate the development of silica-induced lung fibrosis in mice.

Abstract

BACKGROUND:

Silicosis is an occupational lung disease caused by inhalation of silica dust characterized by lung inflammation and fibrosis. Previous study showed that Th1 and Th2 cytokines are involved in silicosis, but Th1/Th2 polarization during the development of silicosis is still a matter of debate. Regulatory T cells (Treg cells) represent a crucial role in modulation of immune homeostasis by regulating Th1/Th2 polarization, but their possible implication in silicosis remains to be explored.

METHODOLOGY/PRINCIPAL FINDINGS:

To evaluate the implication of Treg cells in the development of silicosis, we generated the Treg-depleted mice model by administration of anti-CD25 mAbs and mice were exposed to silica by intratracheal instillation to establish experimental model of silica-induced lung fibrosis. The pathologic examinations show that the Treg-depleted mice are susceptive to severer inflammation in the early stage, with enhanced infiltration of inflammatory cells. Also, depletion of Treg cells causes a delay of the progress of silica-induced lung fibrosis in mice model. Further study of mRNA expression of cytokines reveals that depletion of Tregs leads to the increased production of Th1-cytokines and decreased production of Th2-cytokine. The Flow Cytometry and realtime PCR study show that Treg cells exert the modulation function both directly by expressing CTLA-4 at the inflammatory stage, and indirectly by secreting increasing amount of IL-10 and TGF-β during the fibrotic stage in silica-induced lung fibrosis.

CONCLUSION/SIGNIFICANCE:

Our study suggests that depletion of Tregs may attenuate the progress of silica-induced lung fibrosis and enhance Th1 response and decelerate Th1/Th2 balance toward a Th2 phenotype in silica-induced lung fibrosis. The regulatory function of Treg cells may depend on direct mechanism and indirect mechanism during the inflammatory stage of silicosis.

• Authors: Fangwei Liu, Jie Liu, Dong Weng, Ying Chen, Laiyu Song, Qincheng He, Jie Chen
• Journal: PloS one (PLoS One) Vol. 5 Issue 11 Pg. e15404 (Nov 03 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 21072213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• CTLA-4 Antigen
• CTLA4 protein, human
• Ctla4 protein, mouse
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2
• Interleukin-2 Receptor alpha Subunit
• Interleukin-4
• Silicon Dioxide
• Interferon-gamma

Topics

• Animals
• Antigens, CD (metabolism)
• CTLA-4 Antigen
• Disease Progression
• Female
• Fibrosis
• Flow Cytometry
• Forkhead Transcription Factors (metabolism)
• Gene Expression
• Humans
• Interferon-gamma (genetics)
• Interleukin-2 (genetics)
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Interleukin-4 (genetics)
• Lung (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Pneumonia (chemically induced, immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• Silicon Dioxide
• Silicosis (immunology, pathology)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Th1 Cells (immunology, metabolism)
• Th2 Cells (immunology, metabolism)