Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice

Halvor S. McGee, Arthur L. Stallworth, Tanupriya Agrawal, Zhifei Shao, Lindsey Lorence, Devendra K. Agrawal

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

We previously reported that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c highCD8α highCD11b low dendritic cells and CD4 +CD25 +ICOS +Foxp3 +IL-10 + T-regulatory cells in the lung of allergen-sensitized and -challenged mice. In this study, we evaluated the effect of Flt3-L on Th17 cells and expression of suppressors of cytokine signaling (SOCS) proteins in the lungs of house dust mite (HDM)-sensitized and -challenged mice. BALB/c mice were sensitized and challenged with HDM, and AHR to methacholine was established. Mice were treated with Flt3-L (5 mg, intraperitoneal) daily for 10 days. Levels of IL-4, -5, -6, -8, and -13, and transforming growth factor (TGF)-β in the bronchoalveolar lavage fluid (BALF) were examined by ELISA. Flt3-L treatment reversed existing AHR to methacholine and substantially decreased eosinophils, neutrophils, IL-5, -6, -8, and IL-13, and TGF-β levels in the BALF. HDM-sensitized and -challenged mice showed a significant increase in lung CD4 +IL-17 +IL-23R +CD25 - T cells with high expression of retinoic acid-related orphan receptor (ROR)-γt transcripts. However, administration of Flt3-L substantially decreased the number of lung CD4 +IL-17 +IL-23R +CD25 - T cells, with significantly decreased expression of ROR-γt mRNA in these cells. HDM sensitization caused a significant increase in the expression of SOCS-1, -3, and -5 in the lung. Flt3-L treatment abolished the increase in SOCS-1 and SOCS-3 proteins, whereas SOCS-5 expression was significantly reduced. These data suggest that the therapeutic effect of Flt3-L in reversing the hallmarks of allergic asthma in a mouse model is mediated by decreasing IL-6 and TGF-β levels in the BALF, which, in turn, decrease CD4 +IL-17 +IL-23R +ROR-γt +CD25 - T cells and the expression of SOCS-1 and SOCS-3 in the lung of HDM-sensitized and -challenged mice.

Original languageEnglish
Pages (from-to)520-529
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume43
Issue number5
DOIs
StatePublished - Nov 1 2010

Fingerprint

Suppressor of Cytokine Signaling Proteins
Th17 Cells
Pyroglyphidae
Dust
Lung
T-cells
Interleukin-17
Cytokines
Bronchoalveolar Lavage Fluid
Transforming Growth Factors
Methacholine Chloride
Interleukin-5
T-Lymphocytes
Fluids
Interleukin-6
Interleukin-13
Therapeutic Uses
Regulatory T-Lymphocytes
Tretinoin
flt3 ligand protein

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice. / McGee, Halvor S.; Stallworth, Arthur L.; Agrawal, Tanupriya; Shao, Zhifei; Lorence, Lindsey; Agrawal, Devendra K.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 43, No. 5, 01.11.2010, p. 520-529.

Research output: Contribution to journalArticle

@article{de490613d9cd47189cfe831bcc86850b,
title = "Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice",
abstract = "We previously reported that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c highCD8α highCD11b low dendritic cells and CD4 +CD25 +ICOS +Foxp3 +IL-10 + T-regulatory cells in the lung of allergen-sensitized and -challenged mice. In this study, we evaluated the effect of Flt3-L on Th17 cells and expression of suppressors of cytokine signaling (SOCS) proteins in the lungs of house dust mite (HDM)-sensitized and -challenged mice. BALB/c mice were sensitized and challenged with HDM, and AHR to methacholine was established. Mice were treated with Flt3-L (5 mg, intraperitoneal) daily for 10 days. Levels of IL-4, -5, -6, -8, and -13, and transforming growth factor (TGF)-β in the bronchoalveolar lavage fluid (BALF) were examined by ELISA. Flt3-L treatment reversed existing AHR to methacholine and substantially decreased eosinophils, neutrophils, IL-5, -6, -8, and IL-13, and TGF-β levels in the BALF. HDM-sensitized and -challenged mice showed a significant increase in lung CD4 +IL-17 +IL-23R +CD25 - T cells with high expression of retinoic acid-related orphan receptor (ROR)-γt transcripts. However, administration of Flt3-L substantially decreased the number of lung CD4 +IL-17 +IL-23R +CD25 - T cells, with significantly decreased expression of ROR-γt mRNA in these cells. HDM sensitization caused a significant increase in the expression of SOCS-1, -3, and -5 in the lung. Flt3-L treatment abolished the increase in SOCS-1 and SOCS-3 proteins, whereas SOCS-5 expression was significantly reduced. These data suggest that the therapeutic effect of Flt3-L in reversing the hallmarks of allergic asthma in a mouse model is mediated by decreasing IL-6 and TGF-β levels in the BALF, which, in turn, decrease CD4 +IL-17 +IL-23R +ROR-γt +CD25 - T cells and the expression of SOCS-1 and SOCS-3 in the lung of HDM-sensitized and -challenged mice.",
author = "McGee, {Halvor S.} and Stallworth, {Arthur L.} and Tanupriya Agrawal and Zhifei Shao and Lindsey Lorence and Agrawal, {Devendra K.}",
year = "2010",
month = "11",
day = "1",
doi = "10.1165/rcmb.2009-0241OC",
language = "English",
volume = "43",
pages = "520--529",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

}

TY - JOUR

T1 - Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice

AU - McGee, Halvor S.

AU - Stallworth, Arthur L.

AU - Agrawal, Tanupriya

AU - Shao, Zhifei

AU - Lorence, Lindsey

AU - Agrawal, Devendra K.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - We previously reported that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c highCD8α highCD11b low dendritic cells and CD4 +CD25 +ICOS +Foxp3 +IL-10 + T-regulatory cells in the lung of allergen-sensitized and -challenged mice. In this study, we evaluated the effect of Flt3-L on Th17 cells and expression of suppressors of cytokine signaling (SOCS) proteins in the lungs of house dust mite (HDM)-sensitized and -challenged mice. BALB/c mice were sensitized and challenged with HDM, and AHR to methacholine was established. Mice were treated with Flt3-L (5 mg, intraperitoneal) daily for 10 days. Levels of IL-4, -5, -6, -8, and -13, and transforming growth factor (TGF)-β in the bronchoalveolar lavage fluid (BALF) were examined by ELISA. Flt3-L treatment reversed existing AHR to methacholine and substantially decreased eosinophils, neutrophils, IL-5, -6, -8, and IL-13, and TGF-β levels in the BALF. HDM-sensitized and -challenged mice showed a significant increase in lung CD4 +IL-17 +IL-23R +CD25 - T cells with high expression of retinoic acid-related orphan receptor (ROR)-γt transcripts. However, administration of Flt3-L substantially decreased the number of lung CD4 +IL-17 +IL-23R +CD25 - T cells, with significantly decreased expression of ROR-γt mRNA in these cells. HDM sensitization caused a significant increase in the expression of SOCS-1, -3, and -5 in the lung. Flt3-L treatment abolished the increase in SOCS-1 and SOCS-3 proteins, whereas SOCS-5 expression was significantly reduced. These data suggest that the therapeutic effect of Flt3-L in reversing the hallmarks of allergic asthma in a mouse model is mediated by decreasing IL-6 and TGF-β levels in the BALF, which, in turn, decrease CD4 +IL-17 +IL-23R +ROR-γt +CD25 - T cells and the expression of SOCS-1 and SOCS-3 in the lung of HDM-sensitized and -challenged mice.

AB - We previously reported that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c highCD8α highCD11b low dendritic cells and CD4 +CD25 +ICOS +Foxp3 +IL-10 + T-regulatory cells in the lung of allergen-sensitized and -challenged mice. In this study, we evaluated the effect of Flt3-L on Th17 cells and expression of suppressors of cytokine signaling (SOCS) proteins in the lungs of house dust mite (HDM)-sensitized and -challenged mice. BALB/c mice were sensitized and challenged with HDM, and AHR to methacholine was established. Mice were treated with Flt3-L (5 mg, intraperitoneal) daily for 10 days. Levels of IL-4, -5, -6, -8, and -13, and transforming growth factor (TGF)-β in the bronchoalveolar lavage fluid (BALF) were examined by ELISA. Flt3-L treatment reversed existing AHR to methacholine and substantially decreased eosinophils, neutrophils, IL-5, -6, -8, and IL-13, and TGF-β levels in the BALF. HDM-sensitized and -challenged mice showed a significant increase in lung CD4 +IL-17 +IL-23R +CD25 - T cells with high expression of retinoic acid-related orphan receptor (ROR)-γt transcripts. However, administration of Flt3-L substantially decreased the number of lung CD4 +IL-17 +IL-23R +CD25 - T cells, with significantly decreased expression of ROR-γt mRNA in these cells. HDM sensitization caused a significant increase in the expression of SOCS-1, -3, and -5 in the lung. Flt3-L treatment abolished the increase in SOCS-1 and SOCS-3 proteins, whereas SOCS-5 expression was significantly reduced. These data suggest that the therapeutic effect of Flt3-L in reversing the hallmarks of allergic asthma in a mouse model is mediated by decreasing IL-6 and TGF-β levels in the BALF, which, in turn, decrease CD4 +IL-17 +IL-23R +ROR-γt +CD25 - T cells and the expression of SOCS-1 and SOCS-3 in the lung of HDM-sensitized and -challenged mice.

UR - http://www.scopus.com/inward/record.url?scp=78149343572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78149343572&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2009-0241OC

DO - 10.1165/rcmb.2009-0241OC

M3 - Article

VL - 43

SP - 520

EP - 529

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 5

ER -