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PubMed1996

Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain.

Interleukin-13 (IL-13) is a cytokine secreted by activated T lymphocytes that shares many, but not all, biological activities with IL-4. These overlapping activities are probably due to the existence of common receptor components. Two proteins have been described as constituents of the IL-4 receptor, a approximately 140-kDa glycoprotein (IL-4R) and the gamma chain (gammac) of the IL-2 receptor, but neither of these proteins binds IL-13. We have cloned a cDNA encoding an IL-13 binding protein (IL-13R) from the Caki-1 human renal carcinoma cell line. The cloned cDNA encodes a 380-amino acid protein with two consensus patterns characteristic of the hematopoietic cytokine receptor family and a short cytoplasmic tail. The IL-13R shows homology with the IL-5 receptor, and to a lesser extent, with the prolactin receptor. COS-7 cells transfected with the IL-13R cDNA bind IL-13 with high affinity but do not bind IL-4. COS-7 cells co-transfected with the cloned IL-13R cDNA and IL-4R cDNA resulted in the reconstitution of a small number of receptors that recognized both IL-4 and IL-13. Reverse transcription-polymerase chain reaction analysis detected the receptor transcript only in cell lines known to bind IL-13.

Amino Acid Sequence↗
PubMed1996

Receptor for interleukin (IL) 13 does not interact with IL4 but receptor for IL4 interacts with IL13 on human glioma cells.

Recently, we have demonstrated that human (h) glioma cell lines express large number of receptors (R) for interleukin 13 (IL13) (Debinski, W., Obiri, N. I., Powers, S. K., Pastan, I., and Puri, R. K. (1995) Clin. Cancer Res. 1, 1253-1258). These cells are extremely sensitive to a chimeric protein composed of hIL13 and a derivative of Pseudomonas exotoxin (PE), PE38QQR. We have found that the cytotoxicity of hIL13-PE38QQR was blocked by hIL13 but not by hIL4 on the U-251 MG and U-373 MG cells, contrary to what was observed on several adenocarcinoma cell lines. In the present study, we further explored interactions between receptor for IL13 and IL4 on glioma cells. Established human glioma cell lines, such as DBTRG MG, Hs 683, U-87 MG, SNB-19, and A-172, are very susceptible to hIL13-PE38QQR, and the action of the chimeric toxin is not blocked by hIL4 on all these cells either. Also, hIL4 is not a competitor for 125I-hIL13 binding sites on glioma cells. Of interest, a corresponding hIL4-based chimeric toxin, hIL4-PE38QQR, is poorly active or not active on all the tested glioma cell lines. When active, however, hIL4 toxin action was blocked by hIL13. hIL13 is a competitor for 125I-hIL14 binding in a competitive binding assay on glioma cells. hIL13 and hIL4 did not affect the growth of the tested glioma cell lines. Human glioblastoma multiforme explant cells exhibited similar responses to the chimeric toxins and interleukins when compared with that found in established glioma cultures. Our results suggest that the hIL13R on glioma cells is expressed in one predominant form, the form that does not interact with IL4. Thus, this type of hIL13R is apparently different from the one demonstrated previously on several adenocarcinoma cell lines.

ADP Ribose Transferases↗
PubMed1996

cDNA cloning and characterization of the human interleukin 13 receptor alpha chain.

We have cloned cDNAs corresponding to the human interleukin 13 receptor alpha chain (IL-13Ralpha). The protein has 76% homology to murine IL-13Ralpha, with 95% amino acid identity in the cytoplasmic domain. Only weak IL-13 binding activity was found in cells transfected with only IL-13Ralpha; however, the combination of both IL-13Ralpha and IL-4Ralpha resulted in substantial binding activity, with a Kd of approximately 400 pM, indicating that both chains are essential components of the IL-13 receptor. Whereas IL-13Ralpha serves as an alternative accessory protein to the common cytokine receptor gamma chain (gammac) for IL-4 signaling, it could not replace the function of gammac in allowing enhanced IL-2 binding activity. Nevertheless, the overall size and length of the cytoplasmic domain of IL-13Ralpha and gammac are similar, and like gammac, IL-13Ralpha is located on chromosome X.

Amino Acid Sequence↗
PubMed1997

Identification, purification, and characterization of a soluble interleukin (IL)-13-binding protein. Evidence that it is distinct from the cloned Il-13 receptor and Il-4 receptor alpha-chains.

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are structurally and functionally related cytokines which play an important role in the regulation of the immune response to infection. The functional similarity of IL-4 and IL-13 can be explained, at least in part, by the common components that form their cell surface receptors, namely the IL-4 receptor alpha-chain (IL-4Ralpha) and the IL-13 receptor alpha-chain (IL-13Ralpha). Soluble forms of the IL-4Ralpha have also been described and implicated in modulating the effect of IL-4. In this paper we describe the presence of a 45,000-50,000 Mr IL-13-binding protein (IL-13BP) in the serum and urine of mice. This protein binds IL-13 with a 100-300-fold higher affinity (KD = 20-90 pM) than does the cloned IL-13Ralpha (KD = 3-10 nM). In addition to this functional difference, the IL-13BP appears to be structurally and antigenically distinct from the IL-13Ralpha. Finally, unlike the cloned receptor, the IL-13BP acts as a potent inhibitor of IL-13 binding to its cell surface receptor, raising the possibility that it may be used to modulate the effects of IL-13 in vivo.

Animals↗
PubMed1997

An interleukin (IL)-13 receptor lacking the cytoplasmic domain fails to transduce IL-13-induced signals and inhibits responses to IL-4.

Interleukin (IL)-13 is a pleiotropic immunoregulatory cytokine that shares many, although not all, of the biological activities of IL-4. The overlapping biological properties of IL-4 and IL-13 appear to be due to the existence of shared components of the receptors, and we and others showed that the IL-4 receptor-alpha is involved in signal transduction paths activated by both. We show here that expression of the IL-13 receptor-alpha in two factor-dependent cell lines, the premyeloid FD5 and the T lymphoid CT4.S, conferred the ability to grow continuously in response to IL-13; to respond to IL-13 with tyrosine phosphorylation of JAK1, Tyk2, IL-4Ralpha, IRS-2, and STAT6; and to respond to IL-4 with tyrosine phosphorylation of Tyk2 in addition to those induced in parental cell lines. Expression of a truncated IL-13 receptor-alpha that lacked the cytoplasmic domain demonstrated that this domain was essential for IL-13-dependent growth and phosphorylation of the above substrates. Expression of this truncated IL-13 receptor also resulted in an inhibition of biochemical and biological responses to IL-4 that was exacerbated by the presence of IL-13. These dominant inhibitory effects indicate that the extracellular domain of the truncated IL-13 receptor competes with gammac for complexes of IL-4 and the IL-4 receptor-alpha, or, when itself bound to IL-13, competes with IL-4 for the IL-4 receptor-alpha.

Animals↗
PubMed1998

Regulation of interleukin-13 receptor constituents on mature human B lymphocytes.

Human B cells stimulated through both their immunoglobulin and CD40 receptors up-regulate 745 +/- 51 interleukin (IL)-13 ligand binding sites with an affinity of 0.91 +/- 0.08 nM within 24 h. IL-13 binds primarily to the IL-13Ralpha1 with subsequent sequestration of the IL-4Ralpha into the complex. IL-13Ralpha1 may also be found in those receptors capable of binding IL-4. gamma chain (gammac) participates in receptors capable of binding IL-4 but is not found in association with bound IL-13. Dimeric receptors composed of the IL-4Ralpha complexed with either the IL-13Ralpha1 or gammac occur simultaneously within defined B cell populations. mRNAs for all receptor constituents are increased subsequent to immunoglobulin stimulation alone, while maximal expression of IL-13Ralpha1 is more dependent upon co-stimulation of immunoglobulin and CD40 receptors. mRNA levels for IL-13Ralpha1 vary over a wider range subsequent to surface stimulation than other receptor components. Although gammac is not bound to IL-13 in B cells under the conditions evaluated, it may influence IL-13 binding by competing with IL-13Ralpha1 for association/sequestration with the IL-4Ralpha chain. IL-13Ralpha2 does not participate in the IL-13 receptor that is up-regulated upon activation of quiescent tonsillar B lymphocytes, although mRNA for the protein may be found in the centroblastic fraction of tonsillar cells.

B-Lymphocytes↗
PubMed1999

Characterization of the cytoplasmic domain of interleukin-13 receptor-alpha.

Interleukin (IL)-13 and IL-4 are pleiotropic immunoregulatory cytokines that share many overlapping biological properties reflecting the fact that both can utilize a receptor complex composed of the IL-4 receptor-alpha (IL-4Ralpha) chain and the IL-13Ralpha chain. The cytoplasmic domain of the IL-13Ralpha is 60 amino acids long and is essential for IL-13-dependent growth. It contains a Pro-rich domain in the membrane-proximal region and two Tyr residues. Here we show that a truncated IL-13Ralpha, lacking the 38 carboxyl-terminal residues but retaining the Pro-rich region, can support IL-13-dependent proliferation, although with reduced efficiency. A Y402F mutant of the cytoplasmic domain of IL-13Ralpha supported normal IL-13-induced growth. However, tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which we show is induced by IL-13 and IL-4 in cells that express the IL-13Ralpha, was significantly reduced. The cytoplasmic domain of IL-13Ralpha was constitutively associated with STAT3, Tyk2, and Janus kinase 1 (JAK1). IL-13-induced tyrosine phosphorylation of IL-13Ralpha in vivo could not be detected using anti-Tyr(P) antibodies. A glutathione S-transferase fusion protein of the cytoplasmic domain of IL-13Ralpha was phosphorylated on tyrosine in vitro by JAK1, JAK3, and Tyk2, although the tyrosine phosphorylation events mediated by Tyk2 and JAK3 were not detectable using anti-phosphotyrosine antibodies. These data, together with the demonstration that IL-13Ralpha associates constitutively with Tyk2 and that Tyr-402 is involved in IL-13-induced phosphorylation of STAT3, suggest that the latter is mediated by Tyk2. Tyrosine phosphorylation of STAT3, which was not necessary for IL-13-induced proliferation, may account for some of the effects of IL-4 and IL-13 on the function of their targets.

Base Sequence↗
PubMed1999

Mutants of interleukin 13 with altered reactivity toward interleukin 13 receptors.

Interleukin 13 (IL13) belongs to a family of cytokines whose members exhibit structural homology, despite amino acid sequence dissimilarity. For example, while of limited sequence homology, IL13 and IL4 share a signaling receptor, IL13/4 receptor, on a variety of human normal cells. However, a subclass of IL4-independent IL13 receptors is overexpressed on certain transformed cells, including human malignant gliomas. We introduced mutations into human (h) IL13 to determine the site(s) involved in interaction with the shared receptor and/or the glioma-associated receptor. This analysis identified at least three protein regions that are needed for signaling through the shared receptor. These regions were localized to alpha-helices A, C, and D and were mainly separate from the region(s) needed to interact with the glioma-associated receptor. Glutamic acids at positions 13 and 16 in hIL13 alpha-helix A, arginine and serine at positions 66 and 69 in helix C, and arginine at position 109 in helix D were found to be important in inducing biological signaling since their specific mutation resulted in loss and/or gain of function phenomena. We demonstrate that the molecular requirements of hIL13 to interact with its respective receptors are generally distinct and can be controlled by mutagenesis of the cytokine.

Base Sequence↗
PubMed1993

An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13-induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors.

Interleukin 4 (IL-4) and IL-13 share many biological functions. Both cytokines promote growth of activated human B cells and induce naive human surface immunoglobulin D+ (sIgD+) B cells to produce IgG4 and IgE. Here we show that a mutant form of human IL-4, in which the tyrosine residue at position 124 is replaced by aspartic acid (hIL-4.Y124D), specifically blocks IL-4 and IL-13-induced proliferation of B cells costimulated by anti-CD40 mAbs in a dose-dependent fashion. A mouse mutant IL-4 protein (mIL-4.Y119D), which antagonizes the biological activity of mouse IL-4, was ineffective. In addition, hIL-4.Y124D, at concentrations of up to 40 nM, did not affect IL-2-induced B cell proliferation. hIL-4.Y124D did not have detectable agonistic activity in these B cell proliferation assays. Interestingly, hIL-4.Y124D also strongly inhibited both IL-4 or IL-13-induced IgG4 and IgE synthesis in cultures of peripheral blood mononuclear cells, or highly purified sIgD+ B cells cultured in the presence of anti-CD40 mAbs. IL-4 and IL-13-induced IgE responses were inhibited > 95% at a approximately 50- or approximately 20-fold excess of hIL-4.Y124D, respectively, despite the fact that the IL-4 mutant protein had a weak agonistic activity. This agonistic activity was 1.6 +/- 1.9% (n = 4) of the maximal IgE responses induced by saturating concentrations of IL-4. Taken together, these data indicate that there are commonalities between the IL-4 and IL-13 receptor. In addition, since hIL-4.Y124D inhibited both IL-4 and IL-13-induced IgE synthesis, it is likely that antagonistic mutant IL-4 proteins may have potential clinical use in the treatment of IgE-mediated allergic diseases.

Antigens, CD↗
PubMed1999

Immunoregulatory roles of interleukin-13 in cattle.

Interleukin-13 (IL-13) is produced predominantly by helper T lymphocytes of the Th2 phenotype and mediates its effects on several immune cells, including B lymphocytes and macrophages, stimulating their proliferation, differentiation, and effector functions. IL-13 activates human B cells but has no detectable activity on murine B lymphocytes, suggesting that the activity of IL-13 varies among species. Our studies show that IL-13 enhances proliferation and differentiation of bovine B cells and upregulates cell surface major histocompatibility complex (MHC) class II expression. We examined mRNA expression of the putative signaling component of the bovine IL-13Ralpha1 homolog in several peripheral blood populations. After stimulation with calcium ionophore and phorbol ester, IL-13Ralpha1 mRNA levels appeared to be downmodulated in T cells, upregulated in macrophages and B cells, and unchanged in neutrophils. Together, these studies begin to provide insight into the relative importance of IL-13 in immunoregulation in cattle.

Adjuvants, Immunologic↗
PubMed2000

Genetic variants of IL-13 signalling and human asthma and atopy.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Adult↗
PubMed1998

IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts.

Subepithelial fibrosis in the bronchi of asthmatics is the result of an irreversible lung fibroblast activation, triggered by cytokines secreted by IL-4- and IL-5-activated inflammatory cells. Here, we provide evidence that human lung fibroblasts (ICIG7 cells) express a single class of high-affinity IL-4 receptor (IL-4R). This receptor is functional and composed of at least the IL-4Ralpha and IL-13Ralpha1 chains in the absence of the IL-2Rgamma chain. The IL-4Ralpha is efficiently internalized at 37 degrees C within 15 min in the presence of IL-4, whereas this process is slower with IL-13. In ICIG7 cells, IL-4 triggers the tyrosine phosphorylation of at least two proteins (110 and 180 kDa), and up-regulates the transcription of c-fos, c-jun and c-myc proto-oncogenes. In addition, the secretion of several cytokines [IL-6, granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor (GM-CSF)] as well as the expression of beta1 integrin and VCAM-1 adhesion molecules are augmented by IL-4. IL-13 displays similar biological activities, but less effectively than IL-4. On the other hand, ICIG7 cells could constitute a lung fibroblast population defined by the spontaneous release of several pro-inflammatory cytokines (IL-6, IL-11 and GM-CSF) and cell surface phenotype (CD4 and Thy-1). Through this peculiar cytokine pattern and the IL-4/IL-13-dependent activities, these cells could act as effector cells in the pathogenesis of asthma, triggering and maintaining the recruitment, homing and activation of bone marrow-derived inflammatory cells, and playing a role in the remodeling process of the airways.

Cell Adhesion Molecules↗
PubMed1998

Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway.

IL-13 and IL-4, pleiotropic immune regulatory cytokines, have been shown to mediate similar prominent effects in human fibroblast cell lines. However, molecular mechanisms for their redundant effects are not known. Here, we have investigated the structure of IL-13 receptors (IL-13R) and molecular mechanisms of signal transduction through IL-13 and IL-4 receptors in non-transformed normal skin fibroblast cell lines. We demonstrate that high-affinity IL-13R is expressed in normal skin fibroblast cell lines. Upon [125I]1L-13 cross-linking, a approximately 60-70 kDa band was observed in sk559 and sk574 fibroblast cell lines. By RT-PCR analysis, mRNA for IL-13R alpha, IL-13R alpha' and IL-4Rbeta chains were expressed; however, the IL-2Rgamma chain, shown to participate and modulate IL-4 and IL-13 binding, was not expressed in any of the cell lines examined. The Janus kinase (JAK)2 and Tyk2 were phosphorylated in response to IL-4 or IL-13 in sk559 and sk574 cell lines. JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied. A signal transduction and activator of transcription (STAT)6 was also activated in response to both IL. An insulin receptor substrate (IRS)-1 was constitutively phosphorylated and its phosphorylation level was augmented in response to both IL. These results suggest that the mechanism of signal transduction through IL-13 and IL-4 receptors in human fibroblast cell lines is similar, and this may, at least in part, be responsible for the redundant effects of these two cytokines. In addition, JAK2 tyrosine kinase instead of JAK3 appears to play a major role in IL-4- and IL-13-induced signal transduction in human fibroblasts.

Affinity Labels↗
PubMed1995

Differential regulation of IL-13 and IL-4 production by human CD8+ and CD4+ Th0, Th1 and Th2 T cell clones and EBV-transformed B cells.

In the present study, the requirements and characteristics for the production of IL-13 by human T cells, T cell clones and B cells were determined and compared with those of IL-4. IL-13 was produced by human CD4+ and CD8+ T lymphocyte subsets isolated from peripheral blood mononuclear cells and by CD4+ and CD8+ T cell clones. CD4+ T cell clones belonging to Th0, Th1-like and Th2-like subsets produced IL-13 following antigen-specific or polyclonal activation. In addition, EBV-transformed B cell lines expressed IL-13 mRNA and produced small amounts of IL-13 protein. Expression of IL-13 mRNA and production of IL-13 protein by peripheral blood T cells and T cell clones was induced rapidly and was relatively long lasting, whereas IL-4 production by these cells was transient. In addition, IL-13 mRNA expression was induced by modes of activation that failed to induce IL-4 mRNA expression. IL-13 shares many biological activities with IL-4 which is compatible with the notion that the IL-13 and IL-4 receptors share a common component required for signal transduction. However, IL-13 lacks the T cell-activating properties of IL-4. Here we have shown that this is related to the fact that T cells fail to bind radiolabeled IL-13 and do not express the IL-13-specific receptor component. Taken together, these results indicate that the differences in expression and biological activities of IL-4 and IL-13 on T cells may have consequences for the relative roles of these cytokines in the immune response.

B-Lymphocytes↗
PubMed1996

Biological activity of IL-4 and IL-13 on human endothelial cells: functional evidence that both cytokines act through the same receptor.

The cytokine IL-4 has unique effects on human endothelial cells. It specifically increases expression of vascular cell adhesion molecule (VCAM)-1 promoting adhesion of lymphocytes but not neutrophils, and causes profound effects on the morphology of endothelial monolayers characterized by formation of cell clusters and the appearance of holes in the cultured monolayer. In this study we show that the effects of IL-13 on human umbilical vein endothelial cells (HUVEC) are indistinguishable from those of IL-4. Both cytokines induce the same morphological changes in cultured HUVEC monolayers which are distinct from any other cytokine. In addition, IL-13 and IL-4 stimulate comparable levels of VCAM-1 expression with similar time kinetics, but at doses 10-fold less than those required for B cell activation and proliferation. Using a combination of mutant IL-4 antagonists and mAb to the IL-4R alpha chain (CD124), we show that expression of IL-4R alpha is essential for HUVEC responses to both IL-4 and IL-13, consistent with this receptor subunit being a component of the receptors for both cytokines. In contrast, the common gamma chain (gamma c), which is a component of the classical IL-4 receptor, was not detected on endothelial cells by flow cytometry or immunogold histochemistry. In addition, RT-PCR showed extremely low or absent gamma c mRNA, consistent with the absence of detectable surface protein. These results strongly suggest that the cytokines IL-4 and IL-13 are both important in modulating endothelial cell function, and may act through a single receptor complex on human endothelial cells that includes the IL-4R alpha chain but not the gamma c chain.

Antibodies, Monoclonal↗
PubMed1998

Expression and localization of the Th2-type cytokine interleukin-13 and its receptor in the placenta during human pregnancy.

PROBLEM: To investigate the expression of the Th2-type cytokine interleukin (IL)-13 and its receptor in human placenta during gestation. METHOD OF STUDY: Expression of IL-13 and its receptor was analyzed by reverse transcriptase (RT)-polymerase chain reaction (PCR), in situ hybridization and immunohistochemistry using human placental samples. RESULTS: IL-13 mRNA was detected by RT-PCR in placental extracts from all stages of gestation. In situ hybridization revealed IL-13 mRNA in first trimester cytotrophoblast and syncytiotrophoblast. Few positive cells were found within decidual sections from the same pregnancy. Immunohistochemistry revealed a similar pattern to in situ hybridization. This was largely absent in second- and third-trimester placentae. IL-13 receptor alpha chain (IL-13R alpha) was detected by immunofluorescence on the surface of leukocytes in first-trimester villous core and decidua. CONCLUSIONS: The expression of IL-13 is spatially and temporally regulated in the placenta, and associated with the close proximity of a receptor-bearing target leukocyte population.

DNA, Complementary↗