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Results for “Interleukin-13 Receptor alpha2 Subunit”

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At least 19 recordsLinked to original sources

PubMed2001

Differential effect of IL-4 and IL-13 on CD44 expression in the Burkitt's lymphoma B cell line BL30/B95-8 and in Epstein-Barr virus (EBV) transformed human B cells: loss of IL-13 receptors on Burkitt's lymphoma B cells.

IL-4 and IL-13, cytokines with similar biological effects may influence growth and progression of B-cell tumors through regulation of key cell surface molecules important in intercellular communications. In this study, we demonstrate that IL-4 and IL-13 exhibited differential effects on CD23 and CD44 expression and binding to hyaluronan in BL30/B95-8, a Burkitt's lymphoma (BL), and MK3.31, an Epstein-Barr virus transformed normal human B cell line (B-LCL). Studies conducted to understand the molecular mechanisms underlying this differential effect show that IL-4 induced phosphorylation of JAK1, JAK3, and STAT6 in BL30/B95-8 cells and of JAK3 and STAT6 in MK 3.31 cells. In contrast, IL-13 failed to induce the phosphorylation of JAK kinases or STAT6 proteins in these cell lines. The inability of BL30/B95-8 cells to respond to IL-13 was attributed to the loss of expression of IL-13R subunits alpha1 and alpha2, a finding confirmed for a number of other BL cell lines examined.

B-Lymphocytes↗

PubMed2003

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor alpha2 chain in vivo.

Interleukin-13 receptor (IL-13R) alpha2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ralpha2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ralpha2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ralpha2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ralpha2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy.

Animals↗

PubMed2001

The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway.

The interleukin-13 receptor (IL-13R) complex is composed of 2 different chains, IL-13Ralpha1 (also known as IL-13Ralpha') and IL-13Ralpha2 (also known as IL-13Ralpha). For a functional IL-13 receptor, the IL-13Ralpha1 chain forms a productive complex with the primary IL-4 binding protein (IL-4Ralpha also known as IL-4Rbeta). However, the function of the IL-13Ralpha2 chain is not clear even though this chain binds IL-13 with high affinity. This study demonstrates that IL-13Ralpha2 can undergo internalization after binding to ligand without causing activation of its signaling pathways. These conclusions were drawn on the basis of (1) internalization of (125)I-IL-13 in Chinese hamster ovarian (CHO-K1) and T98G glioblastoma cells transiently transfected with the IL-13Ralpha2 chain; (2) a recombinant chimeric fusion protein comprising IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin) is specifically cytotoxic to IL-13Ralpha2-transfected CHO-K1 cells in a gene dose-dependent manner, whereas cells transfected with vector alone were not sensitive; and (3) IL-13 did not cause activation of signal transduction and activation of transcription 6 (STAT6) in IL-13Ralpha2-transfected cells. IL-13 efficiently caused activation of STAT6 protein in cells transfected with the IL-13Ralpha1 and IL-4Ralpha chains, and IL-13Ralpha2 inhibited this activation. Taken together, these observations indicate that internalization of IL-13Ralpha2 is signal independent and that this property of IL-13Ralpha2 can be exploited for receptor-directed cancer therapy.

Animals↗

PubMed1998

The interleukin-4/interleukin-13 receptor of human synovial fibroblasts: overexpression of the nonsignaling interleukin-13 receptor alpha2.

Interleukin (IL)-4 and IL-13 are known to bind to shared heteromultimeric receptor complexes of variable composition. Given the many regulatory effects of IL-4 and IL-13 on synovial cells, we aimed to characterize their IL-4/IL-13 receptor (R). Cultivated synovial fibroblasts expressed transcripts for IL-4Ralpha and IL-13Ralpha1, the human homolog of the recently cloned mouse IL-13R, but not the common gamma-chain of the IL-2R. In particular, IL-13Ralpha2 mRNA, encoding a different IL-13R recently cloned from human renal carcinoma cells, was expressed at a strikingly high level. Correspondingly, a predominant protein migrating at 65 to 75 kd was cross-linked by iodinated IL-13 and was not cross-competed by an excess of unlabeled IL-4. However, by flow cytofluorometry, IL-13Ralpha1 (detected by the anti-lL-13Ralpha1 mAb 65) and IL-4Ralpha (detected by the mAb S697) were expressed at similar low density. Radioligand binding studies revealed for both cytokines approximately 300 receptors/cell with similar high affinity. An additional class of IL-13Rs was identified after occupation of the shared high-affinity receptors by the nonsignaling, double-mutant IL-4121R-->D, 124Y-->D (RY-IL-4). In these experiments, 1251-IL-13 bound to a single receptor population with a Kd of approximately 300 pM and approximately 5000 sites/cell, matching the published affinity of monomeric IL-13Ralpha2 when expressed in COS7 cells. RY-IL-4 blocked the IL-4- and IL-13-mediated vascular cell adhesion molecule (VCAM)-1 expression and Stat6 activation, suggesting that the large number of high-affinity IL-13Ralpha2 monomers are silent receptors, likely representing a decoy target for IL-13.

Carrier Proteins↗

PubMed2002

Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain.

PURPOSE: Interleukin 13 receptor alpha2-chain (IL-13Ralpha2) has been reported to be abundantly and specifically overexpressed in glioblastoma multiforme. Here we report the identification of a CTL epitope derived from the IL-13Ralpha2. EXPERIMENTAL DESIGN: Mature dendritic cells (DCs) were pulsed with each of the synthetic peptides that were designed, based on a binding affinity-based prediction and a proteosomal cleavage site prediction system, and used to stimulate autologous CD8+ T cells from an HLA-A2+ healthy donor. After four to six cycles of restimulation, the immunoreactivity of the T cells was analyzed for specific IFN-gamma production and CTL reactivity. RESULTS: Of the five peptides tested, IL-13Ralpha(345-354) (WLPFGFILI) induced a CD8(+) T-cell line that specifically produced IFN-gamma in response to HLA-A2+ T2 cells pulsed with the relevant peptide and lysed these cells. Peptide titration assays demonstrated that half-maximal lysis of IL-13Ralpha(345-354) peptide-reactive CD8(+) T cells required peptide loading concentration of approximately 5 nM. Perhaps most importantly, this CD8(+) T-cell line also displayed lytic activity against the HLA-A2+ human glioma cell lines that express IL-13Ralpha2. CONCLUSIONS: This novel CTL epitope may therefore serve as an attractive component of peptide-based vaccines to treat glioma and as a surrogate marker of T-cell immune responses in patients before and after therapy.

Amino Acid Sequence↗

PubMed1997

Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex.

The human homologue of the recently cloned murine IL-13 binding protein (IL-13R alpha1) was cloned from a cDNA library derived from the carcinoma cell line CAKI-1. The cloned cDNA encodes a 427 amino acid protein with two consensus patterns characteristic of the hematopoietic cytokine receptor family and a short cytoplasmic tail. The human protein is 74% identical to the murine IL-13R alpha1, and 27% identical to the human IL-13R alpha2. CHO cells expressing recombinant hIL-13R alpha1 specifically bind IL-13 (Kd approximately 4 nM) but not IL-4. Co-expression of the cloned cDNA with that of IL-4R alpha resulted in a receptor complex that displayed high affinity for IL-13 (Kd approximately 30 pM), and that allowed cross-competition of IL-13 and IL-4. Electrophoretic mobility shift assay showed that IL-13 and IL-4 were able to activate Stat6 in cells expressing both IL-4R alpha and IL-13R alpha1, while no activation was observed in cells expressing either one or the other alone.

Amino Acid Sequence↗

PubMed2003

Expression and characterization of recombinant canine IL-13 receptor alpha2 protein and its biological activity in vitro.

Our previous study showed that recombinant canine IL-13 (rcaIL-13) stimulated production of allergen-specific IgE in vitro by peripheral blood mononuclear cells (PBMC) from flea allergen-sensitized dogs. This has also been demonstrated using human IL-13 (huIL-13) and PBMC isolated from human allergy patients. The stimulatory activity of rcaIL-13 was specifically inhibited by a fusion protein of the extracellular domain of canine IL-13Ralpha2 and the Fc fragment of canine IgG heavy chain (rcaIL-13Ralpha2-Fc). In this communication, we report the construction and expression of a non-fused recombinant extracellular domain of canine IL-13Ralpha2 (rcaIL-13Ralpha2) in an E. coli expression system. The E. coli expressed rcaIL-13Ralpha2 was isolated in inclusion bodies, then solubilized in buffer containing denaturants and reducing agents. After refolding and purification, the biological activity of rcaIL-13Ralpha2 was found in the monomer fraction resulting from gel filtration and ion exchange chromatographies. Biological activity of purified rcaIL-13Ralpha2 was demonstrated by the specific inhibition of rcaIL-13 activity in a TF-1 cell proliferation assay. Additionally, rcaIL-13Ralpha2 was found to be active in neutralizing rcaIL-13 induced upregulation of IgE mRNA levels in PBMCs of "high IgE" dogs, which have been bred to exhibit a predisposition for high IgE production and are used as a model for allergic asthma. The data confirm our previous report that the regulatory effects of IL-13 on IgE production in canine PBMCs are similar to those reported in humans. Thus, allergic dogs, such as the "high IgE" producing dogs, may be excellent models for research on IgE-mediated diseases in humans.

Allergens↗

PubMed2001

Molecular cloning of canine IL-13 receptor alpha chain (alpha1 and alpha2) cDNAs and detection of corresponding mRNAs in canine tissues.

This communication reports the cloning of cDNAs encoding two canine IL-13 receptor alpha chains (caIL-13Ralpha1 and caIL-13Ralpha2). As described for the members of type-I cytokine receptors, both caIL-13Ralpha1 and caIL-13Ralpha2 were found to contain the highly conserved motifs, such as cysteine and tryptophan residues in their N-terminal portion and the WSXWS at C-terminus. The isolated caIL-13Ralpha1 cDNA contains 1547 nucleotides with an open reading frame that encodes 405 amino acid residues. Canine IL-13Ralpha1 is 82.0 and 69.3% identical to human and mouse IL-13Ralpha1s, respectively, at the amino acid level. Canine IL-13Ralpha1 has an almost identical cytoplasmic domain to its human and mouse counterparts. The isolated caIL-13Ralpha2 cDNA contains 1454 nucleotides and encodes an open reading frame of 386 amino acid residues. Canine IL-13Ralpha2 is 62.6 and 47.5% identical to its human and mouse counterparts, respectively, at the amino acid level. Using RT-PCR with caIL-13Ralpha1 and caIL-13Ralpha2 specific primers, mRNAs of caIL-13Ralpha1 and caIL-13Ralpha2 were detected in most dog tissues. In addition, RT-PCR detected caIL-13Ralpha1 mRNA in one of two canine mastocytoma (C2 but not Br) cell lines and in a canine macrophage-derived cell line (DH82). CaIL-13Ralpha2 mRNA was detected in all three canine cell lines.

Amino Acid Sequence↗

PubMed2001

Recombinant canine IL-13 receptor alpha2-Fc fusion protein inhibits canine allergen-specific-IgE production in vitro by peripheral blood mononuclear cells from allergic dogs.

Human IL-13, like IL-4, is involved in the regulation of B-cell development, IgE synthesis and allergic responses. However, because IL-13 does not affect either murine Ig class switching or IgE production in vitro, the use of murine models to study the role of IL-13 in IgE-mediated diseases has been limited. In this communication, we report that recombinant protein of canine IL-13 (rcaIL-13) stimulates production of allergen-specific-IgE in vitro by peripheral blood mononuclear cells (PBMC) from flea allergen-sensitized dogs, and that this stimulation activity is specifically inhibited by recombinant protein of canine IL-13Ralpha2 and Fc fragment of canine IgG heavy chain (rcaIL-13Ralpha2-Fc). The data suggest that the regulatory effects of IL-13 on IgE production in canine PBMC are similar to those reported in humans. Thus, canine IL-13 may be a central mediator of allergic diseases in dogs, and allergic dogs may be excellent models for research on IgE-mediated diseases in humans.

Amino Acid Sequence↗

PubMed2001

Gene transfer of interleukin 13 receptor alpha2 chain dramatically enhances the antitumor effect of IL-13 receptor-targeted cytotoxin in human prostate cancer xenografts.

IL-13Ralpha2 chain, the primary interleukin-13 (IL-13) binding protein, plays an important role in IL-13 binding and internalization. Based on these findings, in our previous study we transiently transfected four cancer cell lines that do not express IL-13Ralpha2 chain and demonstrated that these cells acquired increased sensitivity to IL-13 receptor-targeted recombinant cytotoxin, IL13-PE38QQR, which is composed of IL-13 and a mutated form of a Pseudomonas exotoxin. Although some prostate cancer cell lines express functional IL-13R, they are not highly sensitive to IL-13 cytotoxin. Here we investigated whether human prostate cancer and normal prostate epithelial cell lines express IL-13Ralpha2 chain and whether they can be sensitized to the cytotoxic effect of IL-13 cytotoxin after transient or stable gene transfer of IL-13Ralpha2 chain. Gene transfer of IL-13Ralpha2 chain improved binding activity of IL-13 and sensitivity to IL-13 cytotoxin in vitro. In vivo experiments demonstrated that gene transfer of IL-13Ralpha2 chain dramatically enhanced the antitumor activity of IL-13 cytotoxin in human prostate cancer xenograft models. These results suggest that IL-13R-targeted cytotoxin therapy of prostate cancer may be dramatically enhanced by gene transfer of IL-13Ralpha2 chain and this strategy, the combination of gene therapy and cytotoxin therapy, may be utilized in the treatment of localized prostate cancer.

ADP Ribose Transferases↗

PubMed2001

Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways.

IL-4 and IL-13 are related cytokines which induce both pro- and anti-inflammatory effects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Ralpha and gammac and only binds IL-4, whereas, in the type II receptor, IL-4Ralpha dimerizes with IL-13Ralpha1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Ralpha2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Ralpha2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Ralpha2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Ralpha2 mRNA expression, but potentiated the effects of IL-4 or IL-13 on IL-13Ralpha2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Ralpha2 mRNA even in absence of stimulation. Our findings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13Ralpha2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process.

Antineoplastic Agents↗

PubMed2003

Functional characterization of IL-13 receptor alpha2 gene promoter: a critical role of the transcription factor STAT6 for regulated expression.

Interleukin (IL)-4 and IL-13 are two structurally and functionally related cytokines that have overlapping but also distinct biological activities. One of the components of the IL-13 receptor, the alpha2 chain (IL-13Ralpha2), has been reported to downregulate the cell responsiveness to IL-13, without affecting IL-4 signaling. Here, we report that TNFalpha synergizes with either IL-4 or IL-13 in inducing the IL-13Ralpha2 chain at both the mRNA and protein levels in the HaCaT human keratinocyte cell line. Further studies by 5'RACE identified as yet undescribed exonic sequences of the IL-13Ralpha2 5'UTR, provided evidence for the expression of alternatively spliced IL-13Ralpha2 transcripts and defined the transcription start of the IL-13Ralpha2 gene. A 1.5 kb region upstream of the first exon of the IL-13Ralpha2 gene displayed basal promoter activity when inserted in a reporter plasmid and transiently transfected in HaCaT cells. This promoter activity was further increased in response to IL-4 and IL-13. Furthermore, by electrophoretic mobility shift assay and site-directed mutagenesis, we showed that the IL-4/IL-13-induced promoter activity depended upon a positively acting STAT6 response element. Finally, TNFalpha was shown to potentiate IL-4/IL-13-induced IL-13Ralpha2 promoter activity when the same reporter construct was studied in stably but not in transiently transfected cells. These results suggest that the synergistic effect of TNFalpha on IL-4/IL-13-induced IL-13Ralpha2 expression is dependent upon chromatin re-modeling events.

5' Flanking Region↗

PubMed2002

Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma.

BACKGROUND: A substantial body of evidence exists to support the pivotal role of IL-13 in the pathogenesis of bronchial asthma. We recently found that a variant of the IL13 gene (Arg110Gln) is genetically associated with bronchial asthma, which is concordant with animal experiments using IL-13 in the development of asthma. OBJECTIVE: To address whether the Gln110 variant of IL13 influences IL-13 function, contributing to the pathogenesis of bronchial asthma, we studied the functional properties of the variant. METHODS: We generated 2 types of recombinant IL-13 proteins, the amino acids of which at 110 were arginine or glutamine, and analyzed the binding affinities with the IL-13 receptors, as well as the stability of the proteins. We further compared the relationship between the genotype and serum levels of IL-13. RESULTS: The variant showed a lower affinity with the IL-13 receptor alpha2 chain, a decoy receptor, causing less clearance. The variant also demonstrated an enhanced stability in both human and mouse plasma. We further identified that asthmatic patients homozygous for the Gln110 variant have higher serum levels of IL-13 than those without the variant. CONCLUSION: These results suggested that the variant might act as a functional genetic factor of bronchial asthma with a unique mechanism to upregulate local and systemic IL-13 concentration in vivo.

Amino Acid Substitution↗

PubMed2001

Identification of distinct roles for a dileucine and a tyrosine internalization motif in the interleukin (IL)-13 binding component IL-13 receptor alpha 2 chain.

Interleukin (IL)-13 receptor alpha2 (IL-13Ralpha2) chain is an essential binding component for IL-13-mediated ligand binding. Recently, we have demonstrated that this receptor chain also plays an important role in the internalization of IL-13. To study the mechanism of IL-13 internalization, we generated mutated IL-13Ralpha2 chains that targeted trileucine residues (Leu(335), Leu(336), and Leu(337)) in the transmembrane domain and a tyrosine motif (Tyr(343)) in the intracellular domain and transfected these cDNAs in COS-7 cells. Cells that expressed a C-terminally truncated IL-13Ralpha2 chain (Delta335) did not bind IL-13, suggesting that the trileucine region modulates IL-13 binding. Truncation of IL-13Ralpha2 chain with a mutation in the trileucine region resulted in significantly decreased internalization compared with wild type IL-13Ralpha2 chain transfected cells. COS-7 cells transfected with tyrosine motif mutants exhibited a similar internalization level compared with wild type IL-13Ralpha2 chain transfected cells; however, dissociation of cell surface IL-13 was faster compared with wild type IL-13Ralpha2 transfectants. These results were further confirmed by determining the cytotoxicity of a chimeric protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE38QQR) to cells that expressed IL-13Ralpha2 chain mutants. We further demonstrate that the IL-13Ralpha2 chain is not ubiquitinated and that internalization of IL-13Ralpha2 did not depend on ubiquitination. Together, our findings suggest that the dileucine motif in the trileucine region and tyrosine motif participate in IL-13Ralpha2 internalization in distinct manners.

ADP Ribose Transferases↗

PubMed2001

In vivo overexpression of IL-13 receptor alpha2 chain inhibits tumorigenicity of human breast and pancreatic tumors in immunodeficient mice.

Interleukin 13 receptor alpha2 (IL-13R(alpha)2) chain is highly expressed on some tumor cell lines and primary cell cultures. This receptor chain plays an important role in ligand binding and internalization. To determine the functional significance of overexpression of this chain, we stably transfected IL-13R(alpha)2 chain in human breast (MDA-MB-231) and pancreatic (PANC-1) cancer cell lines that naturally do not express this chain. There was no difference in growth between vector only transfected and IL-13R(alpha)2 chain transfected cells in vitro. However, surprisingly, in immunodeficient mice, tumorigenicity was profoundly inhibited in IL-13R(alpha)2 chain overexpressing tumors. Because breast tumors that grew later showed loss of IL-13R(alpha)2 gene expression, lack of tumorigenicity correlated positively with IL-13R(alpha)2 chain expression. Inflammatory cells including neutrophils and macrophages were identified in IL-13R(alpha)2 overexpressing regressing tumors and neutrophils were found to produce IL-13. IL-13 showed a modest antitumor activity to IL-13R(alpha)2 chain overexpressing tumors in vitro and in vivo. Furthermore, IL-13R(alpha)2 chain overexpressing tumors constitutively produced IL-8 that has been shown to have antitumor effect. These results establish a novel function of a cytokine receptor chain and further suggest that the presence of this chain on tumor cells by itself may play a key role in tumorigenicity.

Animals↗

PubMed2003

Regulation and function of the interleukin 13 receptor alpha 2 during a T helper cell type 2-dominant immune response.

Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R)alpha2 is a critical down-regulatory factor of IL-13-mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13Ralpha2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13Ralpha2-deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13Ralpha2-deficient mice were treated with a soluble IL-13Ralpha2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13Ralpha2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response.

Animals↗

PubMed2002

Effects of IL-13 on airway responses in the guinea pig.

Levels of interleukin (IL)-13 are increased in asthmatic airways. IL-13 has been shown to be necessary and sufficient for allergen-induced airway hyperresponsiveness and increased inflammatory cell counts in bronchoalveolar lavage (BAL) fluid in a murine model of asthma but is thought to protect against airway inflammation when low doses are provided to the guinea pig lung. To determine the role of IL-13 in the guinea pig, we studied the effects of a 360-microg/kg dose of nebulized IL-13 in naive animals and of IL-13 abrogation after airway challenge of sensitized animals. Nebulized IL-13 significantly decreased the dose of histamine required to double baseline respiratory system resistance (ED(100), 22 +/- 3 vs. 13 +/- 2 nmol/kg; P < 0.05) and was associated with recovery of significantly greater numbers of macrophages, lymphocytes, eosinophils, and neutrophils in BAL fluid. Guinea pigs pretreated with a fusion protein that binds IL-13 [soluble IL-13 receptor alpha2 (sIL-13Ralpha2)] were protected from developing antigen-induced airway hyperresponsiveness (ED(100), 210 +/- 50 vs. 20 +/- 10 nmol/kg; P <0.01). sIL-13Ralpha2 (2 doses of 20 mg/kg) significantly reduced the histological grade of allergen-induced lung eosinophil accumulation, whereas the effects of two doses of 10 mg/kg were not significant. These findings demonstrate that the tissue levels of IL-13 induced by allergen challenge of sensitized animals induce airway hyperresponsiveness and inflammation and that IL-13 is required for the expression of allergen-induced airway hyperresponsiveness in the guinea pig ovalbumin model.

Animals↗

PubMed2001

Effects of type 2 cytokines on glomerular epithelial cells.

Visceral glomerular epithelial cells (GECs) are involved in the maintenance of the filtration barrier and may play a role in immune responses. Cytokines may act on GECs and we wished to test this in vitro. Vascular endothelial growth factor (VEGF) is a specific product of the GEC that may play a role in glomerular permeability. We have investigated whether GECs in culture express receptors for interleukin (IL)-4, 10 and 13 (often grouped together as type 2 cytokines) and whether these cytokines alter GEC VEGF production. Type 2 cytokines were compared to transforming growth factor-beta (TGF-beta) and IL-1beta which are known to upregulate VEGF production. GECs were grown from human nephrectomy specimens and cultured with and without the addition of exogenous cytokines. Messenger RNA data demonstrated the presence of IL-4 receptor alpha, IL-10 receptor 1 and 2, and IL-13 receptors alpha1 and alpha2. However, at the protein level by flow cytometry, only IL-13 alpha2 could be consistently demonstrated. IL-4, IL-10 and IL-13 inhibited production of VEGF but did not affect the pattern of isoform expression. In contrast, TBF-beta and IL-1beta caused an increase in VEGF production. These effects were not explained by effects on proliferation. Our data provide evidence that GECs express receptors for type 2 cytokines and that these cytokines can act directly on GECs, to decrease VEGF production.

Cells, Cultured↗