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.
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(high)CD8α(high)CD11b(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 μg, 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.
McGee
Halvor S
HS
Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Stallworth
Arthur L
AL
Agrawal
Tanupriya
T
Shao
Zhifei
Z
Lorence
Lindsey
L
Agrawal
Devendra K
DK
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015704:CD4 Antigens / Q000378:metabolism; D002452:Cell Count; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D008565:Membrane Proteins / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D039981:Pyroglyphidae / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D015704:CD4 Antigens; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D050826:Suppressor of Cytokine Signaling Proteins; C084881:flt3 ligand protein; D016210:Methacholine Chloride