Interleukin 4 induces synthesis of IgE and IgG4 in human B cells (original) (raw)
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Regulation of IgG1 and IgE Synthesis by Interleukin 4 in Mouse B Cells
Scandinavian Journal of Immunology, 1989
Mouse interleukin 4 (lL-4) has been shown to act on B cells as an induction factor for Ig class swilch. We studied ihc characteristics ofIL-4-regulaled Ig isolype production in lipoptilysaccharide(LPS)-slimulated .splenic B-ccllcuUures with emphasis onihe comparison hetwecn the IgGl and IgE responses. The resulis show ihat Ihe kinetics for the appearance of IgG I and IgE isotypes are similar, but that (heilose of lL-4 required for the induction of an IgE response is 3 10 times higher than that for an IgGl response. No requirement forTcelis was found forthemduccion of either isolypc. Pre-incubaiion of cells for 24 h with IL-4 alone was sufticieni to induce an IgGl response when cells were recultured with LPS from days I to 6. However, the simultaneous presence ofboih IL-4 and LPS for at least 24 h was required fora deieciahlc IgE response. For an optimal IgE response. 1 L-4 needed to be present for more than 72 h in LPS-activaied cuhures. The possible reasons for the diflereni regulation of IgG I and IgE responses are discu.ssed.
Proceedings of the National Academy of Sciences, 1988
The effect of human recombinant interleukin 4 (IL-4) on antibody production by normal peripheral blood mononuclear cells enriched for B cells was investigated. IL-4 preferentially induced IgE synthesis in vitro. In addition, a low induction of IgG production was observed, whereas IL-4 had no effect on IgA and IgM synthesis. The IL-4-induced IgE production by B cells required T cells and monocytes but was specifically inhibited by an anti-IL-4 antiserum indicating that, although IL-4 acts indirectly, it is responsible for the induction of IgE synthesis. IL-4-induced IgE production was blocked in a dose-dependent way by interferon gamma (IFN-gamma), interferon alpha (IFN-alpha), and prostaglandin E2. IFN-gamma also inhibited IL-4-induced IgG production. These inhibitory effects of IFN-gamma and IFN-alpha on IgE production cannot be attributed to toxic effects since IFN-alpha induced IgM production in the presence of IL-4, whereas IFN-gamma was ineffective in inhibiting IgG production ...
Clinical & Experimental Immunology, 2008
Using murine monoclonal antibodies .iguinst human IgCi subclasses, specific and sensitive ELISAs assay to quantify the four human IgG subclasses in cell culture supemauints were established. The effect of human recombinant inLerleukin-4 (IL-4) on the regulation of IgG subclasses by normal petipheral blood lymphocytes was investigated. In addition to the enhancement of IgE synthesis. IL-4 preferentially induced IgG4 synthesis in vitro, whereas IL-4 had no effect on IgGI. lgG2, and lgG3 synthesis. lL-4-induced IgG4 production was blocked in a dose-dependent manner by recombinant inlerferon-gamma and anti-human IL-4 monoclonal antibody. Collectively, this data indicates that lL-4 plays an important regulatory role in both IgG subclass and IgR synthe.sis.
European Journal of Immunology, 1988
Frequency analysis of functional Ig C, gene expression in the presence and absence of interleukin 4 in lipopolysaccharide-reactive murine B cells from high and low IgE responder strains* Nonresponder SJL mice produce low levels of antigen-specific IgE after immunization, compared to responder strains. Young athymic BALB/c nude mice are unable to produce antigen-specific or total IgE in their serum. These mice also have very low numbers of background IgE-secreting cells in their lymphoid organs. High-responder BALB/c mice do have substantial numbers of background IgE-secreting cells while low-responder AKR mice show intermediate numbers. Similar differences were found when analyzing lipopolysaccharide (LPS)-reactive B cells in cell suspensions of spleen and bone marrow in limiting dilution cultures. Limiting dilution analysis of T cell-depleted splenic B cell cultures revealed that the defective IgE production in SJL mice is not due to an intrinsic B cell defect. This defect can be substantially overcome by addition of exogenous interleukin 4 (IL4) to these cultures. Furthermore, it was shown in limiting dilution cultures that SJL thymocyte feeder cells were able to suppress IgE production by LPS-activated high-responder BALB/c B cells. The addition of IL 4 or neutralizing antibodies against IL 4 or interferon-y to these cultures helped to overcome this suppressive effect to a large extent. We conclude that different IgE responder types are caused, at least in part, by a defective IL4 production or by a defect in the TH2 system that is functionally detectable at the level of thymocytes.
Functional significance of IL-4 receptor on B cells in IL-4-induced human IgE production
Journal of Allergy and Clinical Immunology, 1995
IL-4 with the IgE-inducing activity is shown to upregulate the expression of IL-4 receptor (IL-4R) on lymphocytes. Antisense strategy was used that aimed at investigating the significance of IL-4-induced upregulation of IL-4R on B cells in human IgE production. When an antisense phosphorothioate oligodeoxynucleotide to IL-4R (S-oligo 1) was added to B cells together with IL-4, the agent selectively abrogated the upregulation of lL-4R without affecting its constitutive level expression. Moreover, S-oligo 1 had a suppressive effect on the T-cell-independent synthesis of lgE by B cells costimulated with IL-4 and anti-CD40 antibody. This suppression was accompanied by inhibition of mature but not germline Ce transcription. These findings indicate that constitutively expressed IL-4R provides a signal or signals responsible for the induction of germline Ce transcription and suggest that IL-4R upregulation may be required for the subsequent class switch recombination that leads to mature Ce transcription and IgE synthesis.
Prolonged In Vivo IL-4 Treatment Inhibits Antigen-Specific IgG1 and IgE Formation
Scandinavian Journal of Immunology, 1994
IL-4 is obligatory for primary IgE responses, whereas primary IgGi and secondary IgE responses are partially IL-4 independent. To investigate the effect of IL-4 on the antigen-specific memory formation for these isotypes, BALB/c mice were treated after primary TNP-K.LH immunization with recombinant IL-4 for a period of 4 months. This prolonged presence of a high IL-4 level resulted in increased serum levels of total IgG, and IgE, whereas total IgG2^ did not change. The expression of CD23, but not I-A*", increased on the splenic B cells. IL-4 treatment did not affect the IL-4 production by Con A stimulated spleen cells, whereas it did decrease the IFN-7 production. In the same mice the TNP-specific IgGi and IgE serum levels, however, were decreased. Similar results were found when the antigen was continuously present during the IL-4 treatment. Furthermore, it was shown that IL-4 decreased the formation of IgGj and IgE memory cells. These results point to different effects of IL-4 in regulating antigen-specific and bystander responses.
European Journal of Immunology, 1990
JCr6me Pkne, Rend De Waal Malefijt, Franqoise Rousset and UNICET, Laboratory for Immunological Research, DardiIly In the present study culture conditions resulting in optimal IgE synthesis by mononuclear cells (MNC) isolated from peripheral blood, tonsils or spleens from healthy nonallergic donors were investigated. The highest rate of IgE synthesis was obtained in a two-step culture system in which the MNC were preincubated with interleukin 4 (IL4; 200 U/ml) for 48 h, washed and subsequently incubated with IL4 (200 U/ml) for 9 days. Despite these culture conditions, ILCinduced IgE synthesis varied considerably (1-150 ng/ml) and MNC from 16/70 donors failed to produce IgE. Kinetic studies indicated that IL 4 was required at the onset of the incubation phase. IgE synthesis was reduced by > 95% when addition of IL4 in the incubation period was delayed 24 h or more. ILCinduced IgE synthesis was blocked by interferon-y (IFN-y). This inhibition is most effective when IFNy was added in the 48-h preincubation step or during the first 48 h of the incubation period. Interestingly, IL4 was found to block spontaneous and lectin-or factor-induced IFN-y production by MNC, purified CD3+, CD4+ or CD8+ Tcells.This down-regulatory effect of IL 4 on IFN-y production occurred at the mRNA transcription level. Furthermore, it is shown that IL4 induced the release of soluble CD23 and that recombinant soluble CD23 enhanced IL4induced IgE synthesis, but only when IL 4 was present at suboptimal concentrations. Collectively, our data indicate that IL4 and IFN-y regulate the level of IgE synthesis by influencing each other's activities reciprocally during the first 3 days of the culture. Abbreviations: MNC: Mononuclear cells sCDU: Soluble 2.1 Reagents CD23 SAC: Staphylococcus aureus strain Cowan I Fc&RII/ CDU: Low-affinity receptor for the Fc part of IgE * Ptne, J., Chrttien, I., Britre, F., Rousset, E andDeVries, J. E., 2 Materials and methods Recombinant IL4 (sp. act. lo7 U/mg) and IFN-y (sp. act. lo7 IU/mg) were gifts from Drs. F? Trotta and S. Nagabhushan (Schering Corp., Bloomfield, NJ).The blockingrabbit polyclonal anti-IL4 antibody was raised in our laboratory submitted for publication. 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1990 0014-2980/90/0202-0243$02.50/0 I. Chrktien, J. P h e , F. Brikre et al. Eur.
European journal of …, 1992
In the present study it is demonstrated that human B cells can be induced to switch to IgE production following a contact-mediated signal provided by activated T cell receptor (TcR) y6+, CD4+ and TcR aB+, CD4+ T cell clones and interleukin (IL)-4. The signal provided by these Tcell clones was antigen nonspecific, indicating that the TcR a@/CD3 or TcR y6ICD3 complexes were not involved in theseT-B cell interactions. Activated TcR aP+, CD8+, and TcR y6+, CD4-CD8-, or resting CD4+ T cell clones were ineffective. Intact TcR afl' or TcR y6+, CD4+ T cell clones could be replaced by plasma membrane-enriched fractions isolated from these activated CD4+ T cell clones. In contrast, membranes isolated from resting TcR a@+, CD4+,TcR y6+, CD4+ T cell clones or an Epstein-Barr virus (EBV)-transformed B cell line (EBV-LCL) failed to provide the costimulatory signal that, in addition to IL-4, is required for induction of IgE synthesis. As described for intact CD4+ T cells, CD4+ T cell membranes induced purified surface IgM+ B cells to switch to IgG4-and IgE-but not to IgAproducing cells, excluding the possibility of a preferential outgrowth of IgG4-and IgE-committed B cells. The membrane activity was inhibited by protease or heat treatment. Induction of IgE synthesis by B cells co-cultured with both TcR a@+, CD4+ and TcR y6+, CD4+ T cell clones and membrane preparations of these cells was blocked by anti-class I1 major histocompatibility complex (MHC) monoclonal antibodies (mAb), whereas various anti-CD4 mAb had differential blocking effects. Murine L cells, or EBV-LCL transfected with CD4 could not replace CD4+ T cell clones.These results indicate that, although CD4 and class I1 MHC antigens are required for productive CD4+ T cell clone-B cell interactions, an additional signal, provided by a membrane associated (g1yco)protein that is induced by activation of both TcR ap and TcR y6, CD4+ T cells, is needed for induction of IgE production in the presence of IL-4.