SEARCH · PubMed Health

Results for “Interleukin-13 Receptor alpha1 Subunit”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1994

Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency.

Human interleukin-4 possesses two distinct sites for receptor activation. A signalling site, comprising residues near the C-terminus on helix D, determines the efficacy of interleukin-4 signal transduction without affecting the binding to the interleukin-4 receptor alpha subunit. A complete antagonist and a series of low-efficacy agonist variants of human interleukin-4 could be generated by introducing combinations of two or three negatively charged aspartic acid residues in this site at positions 121, 124, and 125. One of the double variants, designated [R121D,Y124D]interleukin-4, with replacements of both Arg121 and Tyr124 by aspartic acid residues was completely inactive in all analysed cellular responses. The loss of efficacy in [R121D,Y124D]interleukin-4 is estimated to be larger than 2000-fold. Variant [R121D,Y124D]interleukin-4 was also a perfect antagonist for inhibition of interleukin-13-dependent responses in B-cells and the TF-1 cell line with a Ki value of approximately 100 pM. In addition, inhibition of both interleukin-4-induced and interleukin-13-induced responses could be obtained by monoclonal antibody X2/45 raised against interleukin-4Rex, the extracellular domain of the interleukin-4 receptor alpha subunit. These results indicate that efficient interleukin-4 antagonists can be designed on the basis of a sequential two-step activation model. In addition, the experiments indicate the functional participation of the interleukin-4 receptor alpha subunit in the interleukin-13 receptor system.

Antibodies, Monoclonal↗

PubMed1995

Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15.

Interleukin 13 (IL-13) shares many biological properties with IL-4, and although the receptor for IL-4 (IL-4R) has been characterized, the expression and structure of IL-13 receptor are unknown. We report here that human renal cell carcinoma (RCC) cells express large numbers of functional IL-13R. Human B lymphocytes and monocytes expressed a very small number of IL-13R, while resting or activated human T cells expressed little or no IL-13R. IL-4 did not compete for IL-13 binding, while IL-13 competed for IL-4 binding, even though IL-4R and IL-13R are structurally distinct on human RCC cells. IL-13 cross-linked with one major protein that is similar in size to the gamma c subunit of IL-2, -4, -7, -9, and -15 receptors but was not recognized by anti-gamma c or anti-IL-4R antibodies. IL-4, on the other hand, cross-linked with two major proteins, the smaller of which appears to be similar in size to IL-13R and gamma c, but (like the IL-13R) it did not react with anti-gamma c antibody. Although as shown in this study and in previous studies, gamma c is a functional component of IL-4R in lymphoid cells, it does not appear to be associated with IL-4R on RCC cells. Even in the absence of common gamma chain IL-4 and IL-13 were able to up-regulate intracellular adhesion molecule-1 antigen on RCC cells. These data suggest that the interaction of IL-13 with IL-4R does not involve gamma c and IL-13R itself may be a novel subunit of the IL-4R.

Cross Reactions↗

PubMed1993

Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction.

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are two cytokines that are secreted by activated T cells and have similar effects on monocytes and B cells. We describe a mutant form of human interleukin-4 (hIL-4) that competitively antagonizes both hIL-4 and human interleukin-13 (hIL-13). The amino acid sequences of IL-4 and IL-13 are approximately 30% homologous and circular dichroism (CD) spectroscopy shows that both proteins have a highly alpha-helical structure. IL-13 competitively inhibited binding of hIL-4 to functional human IL-4 receptors (called hIL-4R) expressed on a cell line which responds to both hIL-4 and IL-13. Binding of hIL-4 to an hIL-4 responsive cell line that does not respond to IL-13, and binding of hIL-4 to cloned IL-4R ligand binding protein expressed on heterologous cells, were not inhibited by IL-13. hIL-4 bound with approximately 100-fold lower affinity to the IL-4R ligand binding protein than to functional IL-4R. The mutant hIL-4 antagonist protein bound to both IL-4R types with the lower affinity. The above results demonstrate that IL-4 and IL-13 share a receptor component that is important for signal transduction. In addition, our data establish that IL-4R is a complex of at least two components one of which is a novel affinity converting subunit that is critical for cellular signal transduction.

Amino Acid Sequence↗

PubMed1995

The IL-2 receptor gamma c chain does not function as a subunit shared by the IL-4 and IL-13 receptors. Implication for the structure of the IL-4 receptor.

The IL-2 receptor (IL-2R) gamma c subunit is also a component of the receptors for IL-4, IL-7, IL-9, and IL-15. The IL-4R and IL-13R appear to share a common subunit, and gamma c was proposed to be this shared subunit. In this study, we have assessed the relative contribution of gamma c to the mouse IL-4R and IL-13R. The MC/9 mast cell line constitutively expresses gamma c and proliferates to IL-4 and IL-13, but only the response to IL-4 was blocked by anti-gamma c mAbs. After transfection of the IL-4- and IL-13-responsive gamma c-negative B9 plasmacytoma with full length (m gamma) or cytoplasmic-tailless gamma c cDNA (m gamma t), only the proliferative response to IL-4 was affected by the surface expression of these gamma c molecules. The inability of m gamma or m gamma t expression to affect IL-13-induced proliferation by B9 indicates that gamma c does not obviously contribute to the IL-13R and does not function as the shared subunit of the IL-4R and IL-13R. This study suggests that there are two distinct IL-4R, one of which is independent of gamma c.

Animals↗

PubMed1995

The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor.

Interleukin (IL)-13 elicits a subset of the biological activities of the related IL-4. The basis of this functional similarity is that their specific cell-surface receptors (called IL-13R and IL-4R) are distinct, yet are complex and share a common subunit(s). The IL-4R primary binding subunit (called IL-4R alpha) does not by itself bind IL-13. We show that the ability of IL-13 to partially compete for IL-4 binding to some human cell types depended on co-expression of IL-4R and IL-13R. However, IL-13 binding was always associated with IL-4 binding. Hyper-expression of IL-4R alpha on cells expressing both IL-4R and IL-13R decreased their binding affinity for IL-4, abrogated the ability of IL-13 to compete for IL-4 binding, and yet had no effect on IL-13R properties. Anti-human IL-4R alpha monoclonal antibodies which blocked the biological function and binding of IL-4 also blocked the function and binding of IL-13. These data show that IL-4R alpha is a secondary component of IL-13R.

Animals↗

PubMed1996

Interleukin-13 (IL-13) induces IL-1 receptor antagonist gene expression and protein synthesis in peripheral blood mononuclear cells: inhibition by an IL-4 mutant protein.

Interleukin-13 (IL-13) belongs to the IL-4 gene family. Like IL-4, IL-13 induces IL-1 receptor antagonist (IL-1Ra) synthesis with no effect on IL-1beta synthesis. We investigated whether IL-13 induces IL-1Ra synthesis via a pathway similar to IL-4. In human peripheral blood mononuclear cells, IL-13 (1 to 100 ng/mL alone induced IL-1Ra synthesis in a dose-dependent manner. A single amino acid mutant form of IL-4 (hIL4.Yl24D) induced IL-1Ra synthesis, acting as a partial agonist. However, hIL-4.Yl24D inhibited IL-1Ra synthesis induced by either IL-4 or IL-13. IL-13 alone induced accumulation of IL-1Ra mRNA. Furthermore, IL-13 reduced steady- state levels for IL-1beta mRNA but enhanced those for IL-1Ra mRNA in cells stimulated with lipopolysaccharide (LPS) or IL-1alpha. Accordingly, IL-13 suppressed IL-1beta synthesis but enhanced IL-1Ra synthesis in these cells. IL-13 reduced the stability of IL-1beta mRNA (2.9 v 1.7 hours) but failed to modify the stability of IL-1Ra mRNA (2.7 v 2.5 hours). Moreover, IL-13 induced transcriptional activation of the IL-1Ra gene, but reduced IL-1beta gene transcription. Our results suggest that the commonality between IL-13 and IL-4 in inducing IL-1Ra synthesis results from the engagement of a subunit common to both receptors.

Antigens, CD↗

PubMed1995

Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin.

Interleukin-13 (IL-13) and interleukin-4 (IL-4) are related in structure and function and are thought to share a common receptor component. We have investigated the signal transduction pathways activated by these two growth factors, as well as insulin, in cell-lines and primary cells of lymphohemopoietic origin. All three factors induced the tyrosine phosphorylation of a protein of 170 kDa (p170), which coimmunoprecipitated with the p85 subunit of P13'-kinase, via high affinity interactions mediated by the SH2 domains of p85. Antibodies raised against the entire insulin-receptor substrate-1 (IRS-1) protein immunoprecipitated p170 much less efficiently than they did IRS-1 from 3T3 cells. However, antibodies directed against the conserved pleckstrin homology domain of IRS-1 immunoprecipitated both p170 and IRS-1 with similar efficiency, suggesting they share structural similarities in this region. In lymphohemopoietic cells, IL-13, IL-4, and insulin failed to induce increased tyrosine phosphorylation of Shc, or its association with grb2, modification of Sos1, or activation of erk-1 and erk-2 mitogen-activated protein kinases, suggesting that p170 mediates downstream pathways distinct from those mediated by IRS-1. Both IL-13 and IL-4 induced low levels of tyrosine phosphorylation of Tyk-2 and Jak-1. IL-4 also activated the Jak-3-kinase, but, despite other similarities, IL-13 did not. Insulin failed to activate any of the known members of the Janus family of kinases. In that Jak-3 is reported to associate with the IL-2 gamma c chain, these data suggest that the IL-13 receptor does not utilize this subunit. However, both IL-13 and IL-4 induced tyrosine phosphorylation of the IL-4-140 kDa receptor chain, suggesting that this is a component of both receptors in these cells and accounts for the similarities in signaling pathways shared by IL-13 and IL-4.

3T3 Cells↗

PubMed1996

Effects of interleukin-13 on human neutrophil functions.

It was recently shown that interleukin-13 (IL-13) induces the expression and release of the IL-1 decoy receptor (type II) in human neutrophils along with the production of the IL-1 receptor antagonist. In the present study we focused on further studying the modulatory effects of IL-13 on these cells. We found that recombinant human IL-13 (rhIL-13) induces cellular morphological changes in neutrophils that are typical of activated cells. Furthermore, rhIL-13 was shown to increase tyrosine phosphorylation of several neutrophil proteins. We also demonstrate that this cytokine stimulates de novo RNA synthesis in a concentration-dependent fashion as measured by [5-3H]uridine incorporation and that rhIL-13 induces the synthesis of several neutrophil proteins according to high-resolution two-dimensional gel electrophoresis of metabolically [35S]-labeled cells. We observed that the IL-8 levels in the external milieu of IL-13-stimulated cells was almost fivefold increased when compared with control cells. Finally, we observed that rhIL-13 has no significant effect on phagocytosis and apoptosis. Taken together, our results demonstrate that IL-13 is a modulator of several human neutrophil functions. This leads us to conclude that the modulatory role of IL-13 on human neutrophils, a potentially important anti-inflammatory cytokine, is more complex than previously believed. Furthermore, because we show that the synthesis of several as yet unidentified proteins was up-regulated by IL-13, our findings open new avenues of research on the effects of this cytokine on human neutrophils.

Apoptosis↗

PubMed1995

Interleukin 13 suppresses cytokine production and stimulates the production of 15-HETE in PBMC. A comparison between IL-4 and IL-13.

We examined the ability of rIL-13 to regulate rIL-l alpha induced IL-1 beta, IL-1 receptor antagonist (IL-1ra) and IL-8 production in cultured peripheral blood mononuclear cells (PBMC), endothelial cells and fibroblasts. Furthermore we examined whether rIL-13 could influence the production of the arachidonic acid products LTB4, 12-HETE and 15-HETE by PBMC. rIL-1 alpha-stimulated PBMC cultures secreted high levels of IL-1 beta and IL-8; this could be inhibited to the level of unstimulated control cells by co-incubation with rIL-13 (10 ng/ml). IL-13 induced a 3-fold increase of the IL-1ra secretion which was inhibited by rIFN-gamma. In the presence of both rIL-1 alpha and rIL-13, endothelial cells increased IL-8 secretion, whereas dermal fibroblasts remained unchanged. Of the arachidonic acid metabolites examined, the greatest change was observed in the formation of 15-HETE. In unstimulated PBMC cultures the amount of 15-HETE was less than 4 ng/10(6) cells, whereas after addition of rIL-13 we measured a formation of 139 +/- 6.2 ng/10(6) cells. The effect of rIL-13 on the 15-HETE formation in PBMC was abolished by addition of 100 U/ml rIFN-gamma. rIL-13 only induced minor changes in the LTB4 and 12-HETE formation. Compared to IL-4, IL-13 induced a similar alteration of the cytokine cascade and arachidonic acid metabolism, supporting the hypothesis that the two cytokines use a common receptor complex or signal pathway.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1995

IL-13 and IL-4 share signal transduction elements as well as receptor components in TF-1 cells.

IL-13 and IL-4 are growth factors for the human erythroleukemia cell line TF-1. In these cells both cytokines share overlapping binding sites, but the number of sites for IL-13 is half of that for IL-4. Two monoclonal antibodies against the extracellular domain of the IL-4R alpha chain completely abolish the binding of IL-13, although IL-13 does not bind to this chain. Following receptor triggering, IL-13 and IL-4 induce the phosphorylation of a 170 kDa protein, probably the IL-4-induced phosphotyrosine substrate. In addition the phosphorylation of the 170 kDa protein results in its tight association with phosphatidylinositol-3-kinase.

Antibodies, Monoclonal↗

PubMed1996

Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor.

Interleukins 4 (IL-4) and 13 (IL-13) have been found previously to share receptor components on some cells, as revealed by receptor cross-competition studies. In the present study, the cloning is described of murine NR4, a previously unrecognized receptor identified on the basis of sequence similarity with members of the hemopoietin receptor family. mRNA encoding NR4 was found in a wide range of murine cells and tissues. By using transient expression in COS-7 cells, NR4 was found to encode the IL-13 receptor alpha chain, a low-affinity receptor capable of binding IL-13 but not IL-4 or interleukins 2, -7, -9, or -15. Stable expression of the IL-13 receptor alpha chain (NR4) in CTLL-2 cells resulted in the generation of high-affinity IL-13 receptors capable of transducing a proliferative signal in response to IL-13 and, moreover, led to competitive cross-reactivity in the binding of IL-4 and IL-13. These results suggest that the IL-13 receptor alpha chain (NR4) is the primary binding subunit of the IL-13 receptor and may also be a component of IL-4 receptors.

Amino Acid Sequence↗

PubMed1995

A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4.

Chimeric proteins provide a unique opportunity to target therapeutic bacterial toxins to a subset of specific cells. We have generated a new recombinant chimeric toxin composed of human interleukin 13 (hIL13) and a Pseudomonas exotoxin A (PE) mutant, PE38QQR. The hIL13-PE38QQR chimera is highly cytotoxic to cell lines derived from several human epithelial carcinomas such as adenocarcinoma of stomach, colon, and skin. The cytotoxic action of hIL13-PE38QQR, which can only occur upon internalization of ligand-receptor complex, is blocked by an excess of hIL13 but not of hIL2. This action is not solely hIL13-specific because an excess of hIL4 also blocks the cytotoxicity of hIL13-toxin. Conversely, hIL13 blocks the cytotoxicity of a hIL4-PE38QQR chimera. Binding studies showed that hIL13 displaces competitively 125I-labeled hIL4-PE38QQR on carcinoma cells. These results indicate that IL4 and IL13 compete for a common binding site on the studied human cell lines. Despite this competition, hIL4 but not hIL13 decreased protein synthesis in malignant cells susceptible to the cytotoxicity of both hIL13- and hIL4-PE38QQR. Our results suggest that a spectrum of human carcinomas express binding sites for IL13. Furthermore, hIL13 and hIL4 compete reciprocally for a form of the receptor that is internalized upon binding a ligand. Thus, cancer cells represent an interesting model for studying receptors for these two growth factors. Finally, hIL13-PE38QQR may be a useful agent in the treatment of several malignancies.

ADP Ribose Transferases↗

PubMed1995

Characterization and comparison of the interleukin 13 receptor with the interleukin 4 receptor on several cell types.

We describe here the characterization of the interleukin (IL) 13 receptor and a comparison with the IL-4 receptor on different cell types. Several, but not all, of the IL-4 receptor-positive cells showed specific IL-13 binding, which was always completely displaced by IL-4. In the IL-13 receptor-positive cells, the IL-13 either completely or partially displaced the labeled IL-4. Further characterization of the IL-13 receptor in two cell lines, COS-3 and A431, representative of the groups of complete and partial displacement of IL-4 by IL-13, respectively, showed that the IL-13 binds with high affinity (Kd approximately 300 pM) to both cells and that the number of binding sites is, in COS-3 cells, equivalent to that for IL-4 and, in A431 cells, is smaller than that for IL-4. Cross-linking of labeled IL-13 yielded, on COS-3 cells, two affinity-labeled complexes of 220 and 70 kDa, and on A431 cells, one complex of 70 kDa; labeled IL-4 yielded on both cells the same pattern of three complexes of 220, 145, and 70 kDa. Altogether, these results suggest that the IL-13 receptor may be constituted by a subset of the IL-4 receptor complex associated with at least one additional protein.

Affinity Labels↗

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↗

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↗

PubMedDate not supplied

Inhibition of human IgE synthesis in vitro and in SCID-hu mice by an interleukin-4 receptor antagonist.

In the present study, it is shown that a human interleukin (IL)-4 mutant protein (IL-4.Y124D) acts as a potent IL-4 and IL-13 receptor antagonist. Human (h) IL-4.Y124D efficiently inhibits both IL-4- and IL-13-induced IgE production in vitro. In addition, hIL-4.Y124D strongly inhibits ongoing human IgE synthesis in SCID-hu mice. These inhibitory effects are specific, since human IgG levels were not significantly affected. These results confirm the notion that the IL-4 and IL-13 receptor share a common component, which is required for signal transduction. In addition, they show that relatively large antagonistic polypeptides, such as hIL-4.Y124D have potential clinical utility in reducing IgE-mediated allergic diseases.

Animals↗

PubMed1995

IL-4 induces human B cell maturation and IgE synthesis in SCID-hu mice. Inhibition of ongoing IgE production by in vivo treatment with an IL-4/IL-13 receptor antagonist.

The effect of cytokine treatment on the in vivo maturation and Ig isotype switching of human B cells was studied in a modified SCID-hu mouse model. SCID mice, subcutaneously cotransplanted with small fragments of fetal human thymus and bone (SCID-hu BM/T mice) generated all human leukocyte lineages including T and B lymphocytes, macrophages, and granulocytes. All SCID-hu BM/T mice spontaneously produced human IgM and IgG, whereas IgE and IgA were detected in 37 and 80% of the mice, respectively, indicating that productive human T-B cell interactions resulting in Ig isotype switching occur in these mice. Administration of IL-4 to SCID-hu BM/T mice enhanced human B cell maturation, as judged by the increase in the percentages of CD45+, CD19+ bone marrow B cells expressing CD20, CD23, CD40, sIgM, and sIgD. Furthermore, these cells were also functionally more mature because they spontaneously produced human IgG/IgG4 in vitro and could be induced to secrete human IgE by addition of anti-CD40 mAb alone. In contrast, B cells isolated from PBS-treated mice only produced significant Ig levels after stimulation with anti-CD40 mAb in the presence of exogenous IL-4. IL-4 administration also induced human IgE synthesis in 44% of the mice, which had no serum IgE before treatment. More importantly, ongoing human IgE synthesis in SCID-hu BM/T mice was suppressed by > 90% following administration of an IL-4 mutant protein, which acts as an IL-4 and IL-13 receptor antagonist. These results suggest that IL-4/IL-13 receptor antagonists have potential clinical utility in treating human atopic diseases associated with enhanced IgE production.

Animals↗

PubMed1995

IL-4 induces germ-line IgE heavy chain gene transcription in human fetal pre-B cells. Evidence for differential expression of functional IL-4 and IL-13 receptors during B cell ontogeny.

The present study demonstrates that IL-4 induces germ-line IgE heavy chain (epsilon) gene transcription in human fetal splenic mononuclear cells; fetal bone marrow cells; highly purified sorted surface (s) mu+, CD10+, CD19+ immature B cells; and s mu-, cytoplasmic mu+, CD10+, CD19+ pre-B cells derived from human fetal bone marrow. Similar to observations in normal adult B cells, TGF-beta and IFN-gamma inhibited IL-4-induced germ-line epsilon RNA synthesis in fetal pre-B cells, whereas anti-CD40 mAbs and TNF-alpha had enhancing effects, suggesting that the general mechanisms regulating germ-line epsilon transcription in adult B cells and pre-B cells are similar. IL-13 also induced germ-line epsilon RNA synthesis in s mu+, CD10+, CD19+ immature B cells, but the level of transcription induced by IL-13 was significantly less than that induced by IL-4. Anti-CD40 mAbs strongly synergized with both IL-4 and IL-13 in inducing germ-line epsilon RNA synthesis by fetal immature B cells. Interestingly, IL-13 failed to induce germ-line epsilon RNA synthesis in s mu- pre-B cells even in the presence of anti-CD40 mAbs. These distinct effects of IL-4 and IL-13 suggest that functional IL-13R are expressed at a later stage of B cell ontogeny than IL-4R, and that IL-13, in contrast to IL-4, does not regulate pre-B cell differentiation. Given the fact that IL-4 production appears to be enhanced in atopic individuals, the capacity of IL-4 to induce germ-line epsilon transcription in human fetal immature B cells and pre-B cells suggests that commitment of B cell precursors to IgE-producing cells may occur during intrauterine life and may explain the increased IgE production in neonates with a family history of atopy.

Antigens, CD↗