Mechanisms of AllergyCysLT1 receptor upregulation by TGF-β and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4☆,☆☆
Section snippets
Reagents
Human rIL-13, rIFN-γ, and TGF-β1 were obtained from PeproTech Canada, Inc (Ottawa, Ontario, Canada); all cytokine preparations contained <0.1 ng endotoxin per microgram (1 EU/μg); rabbit polyclonal anti-human C-terminal CysLT1R antibody was developed and characterized in collaboration with Cayman Chemical (Ann Arbor, Mich); rabbit IgG isotype control was obtained from Southern Biotechnology Associates (Birmingham, Ala); FITC-conjugated goat anti-rabbit IgG and Rhodamine (TRITC)-conjugated goat
Cytokine-induced CysLT1R protein expression
The expression of CysLT1R protein in cultured human BSMC was investigated by flow cytometry with a specific anti-CysLT1R antibody. BSMC were treated for 24 hours with graded concentrations of TGF-β, IL-4, and IL-13, ranging from 2.5 to 15 ng/mL, and concentrations of IFN-γ ranging from 50 to 200 U/mL. Whereas the basal expression of CysLT1R in cultured BSMC was low, exposure of the cells to TGF-β, IL-13, or IFN-γ markedly increased their expression of the receptor (Fig 1).
Discussion
Our results demonstrate that TGF-β, IL-13, and IFN-γ can upregulate the expression of CysLT1R protein in BSMC. The effect was time- and concentration-dependent. Interestingly, another prototypic TH2-type cytokine, IL-4, had no effect on CysLT1R expression in human BSMC.
IL-13–treated and IFN-γ–treated cells also showed enhanced levels of CysLT1R mRNA expression. In contrast, TGF-β increased receptor protein expression without significantly affecting CysLT1R mRNA expression. These results suggest
References (39)
- et al.
Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and nonatopic subjects with asthma
J Allergy Clin Immunol
(1997) Airway remodeling in asthma: unanswered questions
Am J Respir Crit Care Med
(2000)- et al.
The mechanics of airway narrowing in asthma
Am Rev Respir Dis
(1989) - et al.
A model of airway narrowing in asthma and in chronic obstructive pulmonary disease
Am Rev Respir Dis
(1992) - et al.
A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model
Am J Respir Crit Care Med
(2002) - et al.
Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats
Br J Pharmacol
(1999) - et al.
Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists
Am J Respir Cell Mol Biol
(1998) - et al.
Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma
Am J Respir Cell Mol Biol
(1997) - et al.
Interleukin-13: central mediator of allergic asthma
Science
(1998) New insights into the role of cytokines in asthma
J Clin Pathol
(2001)
IGFBP-3 mediates TGF-beta1-induced cell growth in human airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol
Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types
Am J Respir Cell Mol Biol
Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1)
J Exp Med
Atopic phenotype in children is associated with decreased virus-induced interferon-alpha release
Int Arch Allergy Immunol
Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis
J Immunol
Peripheral blood CD4+ and CD8+ T cell type 1 and type 2 cytokine production in atopic asthmatic and normal subjects
Clin Exp Allergy
An autosome-wide search for loci underlying wheezing age of onset in German asthmatic children identifies a new region of interest on 6q24-q25
Genet Epidemiol
Interferon-gamma modulates cysteinyl leukotriene receptor-1 expression and function in human airway myocytes
Am J Respir Crit Care Med
IL-5 up-regulates cysteinyl leukotriene 1 receptor expression in HL-60 cells differentiated into eosinophils
J Immunol
Cited by (165)
Leukotriene D<inf>4</inf> role in allergic asthma pathogenesis from cellular and therapeutic perspectives
2020, Life SciencesCitation Excerpt :Also, LTD4 induces HB-EGF mRNA expression through an ERK and p38 MAPK signaling pathway [111]. LTD4 alone does not affect DNA synthesis in human airway smooth muscle cells, however, it markedly increases EGF-mediated cell hyperplasia [112] and the IL-13 or TGFβ-mediated proliferation of the bronchial smooth muscle cells through CysLT1R [113]. On the other side, LTD4 has been shown as a potent bronchoconstrictor especially in the guinea pigs because of their bronchial smooth muscle high responsiveness to LTD4 and it is mediated mainly through CysLT1R [114].
IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways
2020, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Thus, the IL-13–induced increase in Ca2+ influx indicates that the alteration in contraction is specific for the G protein–coupled receptor pathway and regulated at the level of Ca2+ mobilization or above. Both IL-13 and IL-4 increased in agreement with previous studies the expression of HRH1 and CYSLTR1 in HASMCs.36,38 Our RNA sequencing confirmed and extended the importance of this phenomenon, by showing for the first time that IL-13 also increases the expression of these receptors in intact human airways.
The Role of Airway Myofibroblasts in Asthma
2019, ChestCitation Excerpt :An interesting potential innovation is the development of inhaled formulations of statins, which would bypass the liver and allow delivery of lower doses to the airways but with greater potency.116 Cysteinyl leukotrienes (CysLTs), such as LTC4, LTD4, and LTE4, induce the release of fibroblast growth factor from alveolar macrophages,117 increase the proliferation and collagen production of fibroblasts,118 and can potentiate smooth muscle cell proliferation119 (Fig 3). LTC4 upregulates TGF-β1 gene expression and increases production of the protein by epithelial cells,120 providing another mechanism whereby CysLTs can stimulate the production of TGF-β1 in the airway and therefore contribute to remodeling.
Urinary Leukotriene E <inf>4</inf> as a Biomarker of Exposure, Susceptibility, and Risk in Asthma: An Update
2018, Immunology and Allergy Clinics of North AmericaEffects of anti-allergic drugs on T cell-mediated nasal hyperresponsiveness in a murine model of allergic rhinitis
2018, Allergology InternationalLipid mediator Leukotriene D<inf>4</inf>-induces airway epithelial cells proliferation through EGFR/ERK1/2 pathway
2018, Prostaglandins and Other Lipid Mediators
- ☆
Supported by a studentship to Karina Espinosa from CONACYT (Mexico), by a Medical School grant from Merck Frosst, and by a grant from the Canadian Institutes for Health Research.
- ☆☆
Reprint requests: Marek Rola-Pleszczynski, MD, Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, 3001 N 12th Ave, Sherbrooke, QC, Canada J1H 5N4.