Regulatory mechanisms of Th2 cytokine–induced eotaxin-3 production in bronchial epithelial cells: possible role of interleukin 4 receptor and nuclear factor–κB

doi:10.1016/S1081-1206(10)61399-3

Annals of Allergy, Asthma & Immunology

Volume 93, Issue 4, October 2004, Pages 390-397

https://doi.org/10.1016/S1081-1206(10)61399-3 Get rights and content

Background

Several cytokine combinations have been shown to induce eotaxins in bronchial epithelium. The mechanism for differential regulation of eotaxin expression remains unclear.

Objective

To investigate the regulatory mechanisms of eotaxin-3 production vs eotaxin-1 production in cultured bronchial epithelium.

Methods

Messenger RNA (mRNA) expression levels of eotaxin-1, eotaxin-2, and eotaxin-3 in a human bronchial epithelial cell line (BEAS-2B) and a normal human bronchial epithelial cell were examined using reverse transcriptase–polymerase chain reaction. Protein production was determined by enzyme-linked immunosorbent assay. Receptor expression was examined by flow cytometry. Phosphorylation of signal transducer and activator of transcription factor 6 (STAT6) was examined by immunoblotting.

Results

Eotaxin-1 and eotaxin-3, but not eotaxin-2, mRNA expressions were induced by stimulation with interleukin (IL) 13 or IL-4. However, eotaxin-3 was the only protein detected after stimulation. A consistent 10-fold difference in the potency of IL-13- and IL-4-mediated induction of eotaxin-3 mRNA expression was observed. Interleukin 4 induced more potent induction of STAT6 phosphorylation compared with IL-13. The BEAS-2B cells were observed to express types 1 and 2 IL-4 receptors. Pretreatment with tumor necrosis factor α enhanced IL-4-induced eotaxin-1, but not eotaxin-3, mRNA expression. An inhibitor of nuclear factor-κB inhibited IL-13- and IL-4-induced eotaxin-1 gene expressions. However, it enhanced eotaxin-3 gene expression.

Conclusions

These results suggest that differences in the potency of IL-13- and IL-4-mediated induction of eotaxin-3 might be explained by expression of types 1 and 2 IL-4 receptors in bronchial epithelium. Differences in eotaxin-1 and eotaxin-3 mRNA and protein expression might be due to differential effects of nuclear factor-κB on gene expression.

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An emerging role for eotaxins in neurodegenerative disease
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Citation Excerpt :
A growing body of evidence also identifies tissue resident macrophages in the lung and intestinal tract as an important source of these mediators [27,28], while scattered papers demonstrate CCL11 production by cells such as adipocytes and chondrocytes [29,30]. Largely based on in vitro experimentation, inflammatory mediators known to induce eotaxin family members in lung epithelial cells or tissue fibroblasts include the Th2-associated cytokines, interleukin (IL)-4 and IL-13, bacterial lipopolysaccharide (LPS), tumor necrosis factor (TNF)-α, and histamine [26,31–34], while known suppressors include dexamethasone, Th1-associated interferon (IFN)-γ, IL-17, bisphosphonates, β2 adrenergic receptor agonists and fumaric acid [23,35–39]. In sum, eotaxins are produced by a wide range of cell types and appear to be under dynamic control of multiple inflammatory mediators.
Eotaxins are C-C motif chemokines first identified as potent eosinophil chemoattractants. They facilitate eosinophil recruitment to sites of inflammation in response to parasitic infections as well as allergic and autoimmune diseases such as asthma, atopic dermatitis, and inflammatory bowel disease. The eotaxin family currently includes three members: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26). Despite having only ~ 30% sequence homology to one another, each was identified based on its ability to bind the chemokine receptor, CCR3. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid of both mice and humans as part of normal aging. In mice, these increases are associated with declining neurogenesis and impaired cognition and memory. In humans, elevated plasma levels of CCL11 have been observed in Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and secondary progressive multiple sclerosis when compared to age-matched, healthy controls. Since CCL11 is capable of crossing the blood-brain barrier of normal mice, it is plausible that eotaxins generated in the periphery may exert physiological and pathological actions in the CNS. Here, we briefly review known functions of eotaxin family members during innate immunity, and then focus on whether and how these molecules might participate in the progression of neurodegenerative diseases.
Effect of San-ao Decoction, a traditional Chinese prescription, on IL-4 treated normal human bronchial epithelium
2010, Journal of Ethnopharmacology
San-ao Decoction (SA) is a classical prescription, clinically employed to treat asthma in Chinese medicine.
The present study was designed to examine whether SA has a protective effect on normal human bronchial epithelium modeled by interleukin-4 (IL-4), in association with eotaxin-3.
SA is made of three traditional Chinese medicines: Herba Ephedrae, Semen Armeniacae amarum and Radix Glycyrrhizae. Apoptosis was measured by fluorescence microscopy and flow cytometry with IL-4 activated NHBE. In addition, eotaxin-3 mRNA's expression was detected by RT-PCR in NHBE stimulated with IL-4.
Fluorescence microscopy and flow cytometry showed that IL-4-induced normal human bronchial epithelium (NHBE) apoptosis, while SA decreased the apoptosis of NHBE with IL-4 stimulation. RT-PCR showed no expression or low expression of eotaxin-3 mRNA on NHBE, IL-4 enhanced the eotaxin-3 mRNA's expression, and that could be decreased by SA.
The results indicate that SA can decrease NHBE's damage and inflammation through reducing eotaxin-3 mRNA expression.
Analysis of eotaxin 1/CCL11, eotaxin 2/CCL24 and eotaxin 3/CCL26 expression in lesional and non-lesional skin of patients with atopic dermatitis
2010, Cytokine
Eotaxins are the chemokines which are highly selective chemotactic agents for eosinophils. The aim of our study was the evaluation of the gene expression level for eotaxin 1/CCL11, eotaxin 2/CCL24, and eotaxin 3/CCL26, both in skin changes and in uninvolved skin of atopic dermatitis (AD) patients. The study comprised 19 patients with AD and 10 healthy controls. The gene expression level for eotaxins in the skin biopsies was evaluated by the real-time quantitative PCR. The change of the gene expression level, calculated as log10 skin lesions/non-lesional skin, was 0.635 for CCL11, 0.172 for CCL24 and 0.291 for CCL26. The change of the gene expression level, calculated as log10 non-lesional skin of AD patients/healthy control, was 0.394 for CCL11, −0.216 for CCL24, and 0.229 for CCL26, while skin lesions of AD patients/healthy control, was: 0.788, −0.046, and 0.483, respectively. Conclusion: The mean gene expression level for CCL11, CCL24, CCL26 was higher in skin changes of AD patients than in uninvolved skin. The higher level of CCL26 in skin changes, indicates its role in their aetiology in AD. The gene expression level for CCL24 in AD patients was lower, both in involved and uninvolved skin vs. the healthy control.
Chemokines
2009, Asthma and COPD
Chemokines have multiple roles in the organization of the immune system under basal conditions and during infection, and are also involved in angiogenesis. A crucial role of chemokines is the recruitment of different types of leukocytes from the blood to the sites of inflammation. Most of the known chemokines belong to two major families defined by the position of four conserved cysteine residues. The largest family is the CC chemokine family (28 in number), which possesses two adjacent cysteines in the vicinity of the N-terminus of the mature peptide. The CXC family (16 members) has two cysteine residues in this same region, but with an interposed amino acid. Chemokines are thought to bind to presenting molecules on the luminal surface of the venular endothelium, such as glycosaminoglycans, where the chemokines engage their receptors on the leukocyte surface. A combination of clinical observations, in vitro cell biology and in vivo animal modeling has delineated potentially important mechanisms underlying lung inflammation in COPD and asthma. These extensive studies support the hypothesis that chemokines have a fundamental role in regulating leukocyte trafficking in inflammatory disease. The chemokine receptors represent novel targets for treatment and therapeutic compounds have been described with efficacy in vitro and in vivo.
Chemokines
2008, Asthma and COPD: Basic Mechanisms and Clinical Management
Chemokines have multiple roles in the organization of the immune system under basal conditions and during infection, and are also involved in angiogenesis. A crucial role of chemokines is the recruitment of different types of leukocytes from the blood to the sites of inflammation. Most of the known chemokines belong to two major families defined by the position of four conserved cysteine residues. The largest family is the CC chemokine family (28 in number), which possesses two adjacent cysteines in the vicinity of the N-terminus of the mature peptide. The CXC family (16 members) has two cysteine residues in this same region, but with an interposed amino acid. Chemokines are thought to bind to presenting molecules on the luminal surface of the venular endothelium, such as glycosaminoglycans, where the chemokines engage their receptors on the leukocyte surface. A combination of clinical observations, in vitro cell biology and in vivo animal modeling has delineated potentially important mechanisms underlying lung inflammation in COPD and asthma. These extensive studies support the hypothesis that chemokines have a fundamental role in regulating leukocyte trafficking in inflammatory disease. The chemokine receptors represent novel targets for treatment and therapeutic compounds have been described with efficacy in vitro and in vivo.
Modulation of eotaxin-3 (CCL26) in alveolar type II epithelial cells
2006, Cytokine
Airway epithelial inflammation associated with emphysema, chronic bronchitis, chronic obstructive pulmonary disease (COPD) and asthma is regulated in part by alveolar type II cell chemokine signaling. Data suggest that resident lung cells use CCR3, CCR5 and CCR2 chemokine receptor/ligand systems to regulate the profile of leukocytes recruited in disease-associated inflammatory conditions. Thus studies were designed to test whether alveolar type II cells possess a Th1-activated CCR5-ligand system that modulates the Th2-activated CCR3/eotaxin-2 (CCL24), eotaxin-3 (CCL26) chemokine systems. The A549 alveolar type II epithelial-like cell culture model was used to demonstrate that alveolar type II cells constitutively express CCR5 which may be upregulated by MIP-1α (CCL3) whose expression was induced by the Th1 cytokines IL-1β and IFN-γ. Selective down-regulation of CCL26, but not CCL24, was observed in CCL3 and IL-4/CCL3 stimulated cells. Down-regulation was reversed by anti-CCR5 neutralizing antibody treatment. Thus, one mechanism through which Th1-activated CCCR5/ligand pathways modulate Th2-activated CCR3/ligand pathways is the differential down-regulation of CCL26 expression. Results suggest that the CCR3 and CCR5 receptor/ligand signaling pathways may be important targets for development of novel mechanism-based adjunctive therapies designed to abrogate the chronic inflammation associated with airway diseases.

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: This study was supported in part by grant C2–14570753 from the Ministry of Education, Science, Sports, and Culture of Japan.

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ORIGINAL ARTICLESRegulatory mechanisms of Th2 cytokine–induced eotaxin-3 production in bronchial epithelial cells: possible role of interleukin 4 receptor and nuclear factor–κB

Background

Objective

Methods

Results

Conclusions

J Biol Chem.

J Biol Chem.

J Allergy Clin Immunol.

Cytokine.

Cell Immunol.

Ann Allergy Asthma Immunol.

J Allergy Clin Immunol.

J Biol Chem.

Cytokine.

Immunological aspects of allergic asthma

Annu Rev Immunol.

Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma

N Engl J Med.

Cytokines and chemoattractants in allergic inflammation

Mol Immunol.

Elemental signals regulating eosinophil accumulation in lung

Immunol Rev.

Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils

J Exp Med.

Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation

J Exp Med.

Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia

Nat Med.

Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes

J Exp Med.

ORIGINAL ARTICLES
Regulatory mechanisms of Th2 cytokine–induced eotaxin-3 production in bronchial epithelial cells: possible role of interleukin 4 receptor and nuclear factor–κB