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The Journal of Immunology, 1998, 161: 1738-1742.
Copyright © 1998 by The American Association of Immunologists

Requirement for Dual Signals by Anti-CD40 and IL-4 for the Induction of Nuclear Factor-{kappa}B, IL-6, and IgE in Human B Lymphocytes1

John D. Jeppson, Hiren R. Patel, Naoki Sakata, Joanne Domenico, Naohiro Terada and Erwin W. Gelfand2

Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Stimulation of human peripheral B cells via the CD40 receptor and IL-4R together lead to IgE synthesis and secretion, but the intracellular signaling mechanisms by which these signals lead to IgE production are unclear. Roles for the transcription factor NF-{kappa}B and IL-6 have been postulated in the induction of IgE synthesis by IL-4/CD40. We found that neither anti-CD40 Ab nor IL-4 alone was able to induce significant proliferation of human B cells. However, the combination of anti-CD40 and IL-4 was a potent inducer of B cell proliferation in addition to IgE production from purified human B cells. Furthermore, IL-4 and anti-CD40 synergized for the production of IL-6. While neither IL-4 alone nor anti-CD40 alone was able to induce significant NF-{kappa}B DNA binding activity, the combination of IL-4 and anti-CD40 induced a strong activation of NF-{kappa}B, a transcription factor that regulates IL-6 production. These data indicate that both IL-4 and anti-CD40 are required to induce NF-{kappa}B activation and IL-6 transcription and production, and implicate these events in a signaling pathway augmenting IgE production in human B lymphocytes.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
CD40 is a surface Ag on B cells and shows homology to a group of surface proteins, including the TNF receptor, the nerve growth factor receptor, and the Fas protein (1, 2). Stimulation of B cells via the CD40 molecule can induce a wide variety of effects on B cells, including growth, differentiation, and rescue from B cell Ag receptor-mediated apoptosis (3, 4). In combination with IL-4, stimulation of CD40 leads to enhanced germline {epsilon} mRNA expression, functional {epsilon} gene transcription, and IgE secretion (5, 6). The intracellular mechanisms by which these surface-generated signals lead to enhanced IgE production remain unclear.

Signaling through CD40 leads to the phosphorylation and/or dephosphorylation of a number of proteins, including the Lyn, Fyn, and Syk tyrosine kinases (7, 8). We have demonstrated that CD40 stimulation of human B cells leads to selective activation of the c-Jun kinase/stress-activated protein kinase pathway (9). Recent evidence has implicated members of the TNF receptor-associated factor (TRAF) family of signal transducers in mediating CD40-generated signals within the cell (10, 11). Furthermore, protein tyrosine kinase inhibitors are able to block the induction of IgE secretion by anti-CD40 and IL-4, suggesting that such phosphorylation events may be critical in mediating the differentiative effects of CD40/IL-4 stimulation of B cells (12). It also has been reported that stimulation of B cells via CD40 leads to activation of the NF-{kappa}B transcription factor (13, 14). However, the relationship between these early signaling events and the later differentiative events of the B cell response to IL-4 and CD40 stimulation has not been defined.

IL-4 induction of IgE secretion in PBMC or T and B cell mixtures appears to require IL-6, as depletion of monocytes from this population strongly diminishes the ability of IL-4 to induce IgE (15). Stimulation of highly purified B cells with IL-4, IL-5, and IL-6 nonetheless does not lead to IgE production, indicating that the second signal provided via CD40 is a requisite step. A neutralizing anti-IL-6 Ab strongly inhibits the ability of anti-CD40 Ab and IL-4 to induce IgE synthesis in highly purified human B cells, suggesting that the autocrine production of IL-6 is a necessary step in CD40-induced IgE production (16).

IL-6 is expressed by a number of cell types and induces a wide variety of responses, including induction of hepatic acute phase responses, differentiation of B cells, and augmentation of T cell responses (17). The expression of IL-6 is regulated primarily through the binding of the NF-{kappa}B transcription factor to IL-6 promoter sequences (18). Stimuli that induce IL-6 gene expression, such as IL-1 and TNF-{alpha}, also induce NF-{kappa}B DNA binding activity (19). Furthermore, the deletion of the NF-{kappa}B sequences within the IL-6 promoter strongly diminishes the induction of IL-6 gene expression (19, 20, 21).

NF-{kappa}B is a pleiotropic transcription factor that is involved in regulating the expression of a number of genes, including Ig light chain, IL-2, and c-myc, in addition to IL-6 (22, 23, 24). NF-{kappa}B is a dimeric complex located in the cytosol in an inactive form associated with an inhibitor, I{kappa}B (25). Cell stimulation by a number of agents leads to the release of NF-{kappa}B from I{kappa}B and its subsequent translocation into the nucleus (26, 27).

Because of the demonstrated synergistic effects of anti-CD40 mAbs and IL-4 on IgE synthesis by purified normal human B cells, we examined whether the signals generated by these two stimuli also synergize to activate additional factors that may be involved in regulating IgE production and secretion, namely NF-{kappa}B and IL-6. We found that IL-4 and anti-CD40 synergized to induce NF-{kappa}B activation and IL-6 production as well as IgE secretion, suggesting that these regulatory events may be involved in the transmission of CD40/IL-4-activated signals to enhance IgE production.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Reagents

G28–5 anti-CD40 mAb was a gift from Dr. Edward Clark (Seattle, WA). Recombinant IL-4 was provided by Paul Trotta (Schering Plough, Kenilworth, NJ). Tritiated thymidine deoxyribonucleotide (6.7 Ci/mmol) and [{alpha}-32P]dCTP (25 Ci/mmol) were purchased from ICN Pharmaceuticals (Irvine, CA). Oligonucleotides containing the consensus NF-{kappa}B binding sequence (5'-GGGAGTTGAGGGGACTTTCCCAGGC) or the consensus AP-13 binding sequence (5'-CTTCGTGACTCAGCGGGATCCTTCGTGACTCAGCGG) were synthesized by the Molecular Resource Center at the National Jewish Center (Denver, CO). IL-6 cDNA (pBSF2.38.1) was provided by Dr. Toshio Hirano (Osaka, Japan) (28). mAbs to p50 (SC-114) and p65 (SC-109) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Streptavidin-fluorescein reagent and biotin-16-dUTP were purchased from Boehringer Mannheim (Indianapolis, IN).

Blood sampling and cell preparations

PBMC were prepared from heparin-treated blood of healthy human volunteers by Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) gradient centrifugation. B cells were purified by E rosette depletion and two-phase plastic adherence as previously described (29). B cells prepared in this manner typically were >95% positive for the B cell markers CD19 and CD20 as determined by flow cytometric analysis. For measurement of IL-6 production by ELISA, purified B cells were resuspended in serum-free medium and incubated for 24 h at 37°C to eliminate potential contamination by IL-6 from the serum. For all other experiments, cells were resuspended in RPMI 1640 tissue culture medium (Life Technologies, Grand Island, NY), supplemented with penicillin (100 U/ml), streptomycin (100 mg/ml), L-glutamine (2 mmol/L), and 10% heat-inactivated FCS.

ELISAs

B cells (1 x 106) were incubated in a total volume of 1 ml in 24-well plates. Cells were stimulated with anti-CD40 mAb (250 U/ml) or IL-4 (200 U/ml) as indicated. Supernatants were harvested after a 14-day culture. ELISA for the determination of total IgE was performed in flat-bottom 96-well plates (Dynatech, Alexandria, CA), coated with purified goat anti-human IgE (Tago, Burlingame, CA) as previously described (30). All cultures were performed in triplicate. The limit of detection in the ELISA was 100 pg/ml for IgE.

IL-6 accumulation measurements

IL-6 accumulation in supernatants was determined using an ELISA kit obtained from R&D Systems (Minneapolis, MN).

Nuclear extracts and electrophoretic mobility shift assay

After stimulation, B cells were lysed in hypotonic buffer, and nuclear proteins were extracted as previously described (31). Nuclear extracts were stored at -70°C until use. Binding reactions were conducted with equal amounts of protein for each experiment (0.2–1.0 µg). A double-stranded oligonucleotide containing the NF-{kappa}B sequence was end labeled with [{alpha}-32P]dCTP using Klenow fragment of DNA polymerase I. Protein samples were incubated at room temperature first with poly(dI-dC) (1 µg) for 10 min and then with the radiolabeled probe for 15 min in a total volume of 15 µl. Samples were analyzed using a 5% polyacrylamide gel under nondenaturing conditions with 1x Tris borate electrophoresis buffer as the running buffer. Following electrophoresis, the gels were dried and analyzed by autoradiography. Films from four separate experiments were scanned, and the densities of the bands were analyzed. Supershift experiments were performed by preincubating nuclear extracts with anti-p50 or anti-p65 Ab for 10 min before addition of radiolabeled DNA probe.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
We initiated a series of experiments using peripheral human B cells to elucidate the mechanisms by which anti-CD40 Ab and IL-4 induce IgE synthesis in these cells. To determine the optimal concentrations of Ab and cytokine, we first measured the ability of these reagents to induce the proliferation of highly purified human B cells as measured by the incorporation of tritiated TdR. We found that neither anti-CD40 Ab nor IL-4 alone was able to induce significant proliferation of human B cells (Fig. 1Go). No proliferation was seen with concentrations of anti-CD40 up to 250 µg/ml or of IL-4 up to 3000 U/ml (data not shown). However, the combination of anti-CD40 at 1 µg/ml and IL-4 at 200 U/ml was a potent inducer of B cell proliferation (Fig. 1Go).



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  		FIGURE 1. Anti-CD40 Ab and IL-4 synergize to induce proliferation of peripheral blood B cells. B cells (1 x 106/ml) were purified from the peripheral blood of normal human donors as described in Materials and Methods and stimulated with rIL-4 (200 U/ml), G28–5 anti-CD40 Ab (1 µg/ml), or both for 48 h. Incorporation of tritiated thymidine into DNA during the final 6 h of culture was measured. The data represent the mean and SEM from three independent experiments.

 
Previous studies have demonstrated that anti-CD40 Ab and IL-4 synergize to induce IgE production by highly purified human B cells (5, 6). We examined whether the concentrations of Ab and cytokine that were optimal in B cell proliferation assays would induce IgE secretion as well. The combination of anti-CD40 Ab (1 µg/ml) and IL-4 (200 U/ml) induced significant IgE production in purified human B cells (Fig. 2Go). Anti-CD40 alone induced no detectable IgE, and IL-4 alone induced only low levels of IgE production.



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  		FIGURE 2. Anti-CD40 Ab and IL-4 synergize to induce IgE secretion by peripheral blood B cells. B cells (1 x 106/ml) were purified from the peripheral blood of normal human donors as described in Materials and Methods and stimulated with rIL-4 (200 U/ml), G28–5 anti-CD40 Ab (1 µg/ml), or both for 14 days. Culture supernatants were analyzed for IgE accumulation by ELISA as described in Materials and Methods. The data represent the mean and SEM from four independent experiments.

 
IL-6 appears to be required for the T cell-dependent induction of IgE production by IL-4 in human peripheral B cells (15). The addition of anti-IL-6 Ab to cultures of human PBMC sharply inhibited the production of IgE production. Therefore, we assessed whether the combination of anti-CD40 Ab and IL-4 was able to induce IL-6 secretion by highly purified human B cells. We found that neither reagent alone was able to induce significant IL-6 secretion (Fig. 3Go). However, the combination of IL-4 and anti-CD40 proved to be a strong inducer of IL-6 secretion in B cells. Further, addition of (up to 5%) monocytes did not alter the levels of IL-6 secretion detected (data not shown).



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  		FIGURE 3. Anti-CD40 Ab and IL-4 synergize to induce IL-6 secretion by peripheral blood B cells. B cells were purified from the peripheral blood of normal human donors as described in Materials and Methods and stimulated at 2 x 105/ml with rIL-4 (250 U/ml), G28–5 anti-CD40 Ab (1 µg/ml), or both for 24 h in serum-free medium. Tissue culture supernatants were analyzed for IL-6 protein accumulation by ELISA as described in Materials and Methods. The data represent the mean and SEM from six independent experiments.

 
The NF-{kappa}B transcription factor has been implicated in the induction of IL-6 gene expression (14). To assess whether the combination of anti-CD40 and IL-4 could induce NF-{kappa}B activity, we prepared nuclear extracts from stimulated human B cells and performed electrophoretic mobility shift assays. As in the other assays, we found that while neither IL-4 alone nor anti-CD40 alone induced NF-{kappa}B DNA binding activity, the combination of IL-4 and anti-CD40 induced a strong activation of NF-{kappa}B (Fig. 4Go and Fig. 5Go) with similar levels of activation at 2 and 4 h of stimulation. As shown in Figure 4Go (lane 1) and Figure 5Go (lane 1), low levels of NF-{kappa}B activity were detected in unstimulated peripheral blood B cells. These results differ from those of a previous report that showed that anti-CD40 Ab alone was able to induce NF-{kappa}B DNA binding activity in purified human B cells (14). However, tonsillar B cells were used in this earlier study, while our experiments were performed with resting, purified peripheral blood B cells. It is possible that these differences in results reflect differences in the activation status of tonsillar compared with peripheral blood B cells (32).



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  		FIGURE 4. Anti-CD40 Ab and IL-4 synergize to activate NF-{kappa}B in peripheral blood B cells. B cells were purified from the peripheral blood of normal human donors as described in Materials and Methods and stimulated at 2 x 106 cells/ml with rIL-4 (250 U/ml), G28–5 anti-CD40 Ab (1 µg/ml), or both for the indicated times. Nuclear extracts were prepared and analyzed for NF-{kappa}B DNA-binding activity by electrophoretic mobility shift assay as described in Materials and Methods. The data are representative of four similar experiments.

 


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  		FIGURE 5. Anti-CD40 Ab and IL-4 synergize to activate NF-{kappa}B in peripheral blood B cells. B cells were purified from the peripheral blood of normal human donors as described in Materials and Methods and stimulated at 2 x 106 cells/ml with rIL-4 (200 U/ml) and G28–5 anti-CD40 Ab (1 µg/ml) for 4 h. Nuclear extracts were prepared and analyzed for NF-{kappa}B DNA-binding activity as described in Materials and Methods. Nuclear extracts were preincubated for 10 min with anti-p65 Abs before the addition of labeled DNA probe. The data are representative of two similar experiments. Lane 1, Unstimulated B cells; lane 2, IL-4, 4 h; lane 3, anti-CD40, 4 h; lane 4, IL-4 plus anti-CD40, 4 h; lane 5, IL-4, anti-CD40, and cold NF-{kappa}B; lane 6, IL-4, anti-CD40, and cold AP-1; lane 7, IL-4, anti-CD40, and anti-p65; lane 8, IL-4, anti-CD40, and anti-c-Jun.

 
To confirm the specificity of the apparent NF-{kappa}B binding induced by anti-CD40 and IL-4, mobility shift assays were performed using unlabeled NF-{kappa}B or unlabeled AP-1 as competitor probes. As shown in Figure 5Go (lanes 5 and 6), unlabeled NF-{kappa}B effectively competed with the labeled NF-{kappa}B probe to eliminate specific NF-{kappa}B binding activity, whereas unlabeled AP-1 probe had no competitive effect on the NF-{kappa}B band.

To confirm that the DNA binding activity induced by anti-CD40 and IL-4 was due to authentic NF-{kappa}B, we performed experiments using Abs to the p65 component of NF-{kappa}B. As shown in Figure 5Go, anti-p65 Ab, but not control Abs, reduced NF-{kappa}B binding. These results confirmed that the DNA binding activity induced by anti-CD40 and IL-4 in purified human B cells was indeed NF-{kappa}B. The combination of anti-p50 and anti-p65 Abs also caused a marked reduction in the NF-{kappa}B band (data not shown).

Stimulation of human B lymphocytes via the CD40 receptor in the presence of IL-4 leads to a marked up-regulation in IgE production and secretion (6). While anti-CD40 Ab is not able to induce germline {epsilon} gene transcription, it does lead to a significant enhancement of germline {epsilon} mRNA production in the presence of IL-4 (5). IL-4 alone is not able to induce switch recombination to the C{epsilon} gene and requires the CD40 signal provided by CD4+ T cells for class switching and functional IgE secretion (33). Furthermore, the observation that the defective expression of gp39 underlies the hyper-IgM syndrome in humans confirms that CD40 signaling plays an integral role in all Ig gene switching (34, 35, 36, 37, 38, 39).

Stimulation of B lymphocytes by cross-linking the B cell Ag receptor complex with anti-IgM leads to programmed cell death. Activation of the CD40 receptor rescues such anti-IgM-stimulated cells from undergoing apoptosis (3). It has been suggested that the activation of the zinc finger protein, A20, by CD40 leads to the prevention of programmed cell death (40). Others have suggested that the bcl-x gene product plays an important role in CD40 modulation of the apoptotic response of B lymphocytes (41, 42). Recently, CD40 ligation has been shown to prevent the anti-IgM-induced activation of CPP32, one of the caspases known to deliver a death signal (43). Our observation that anti-CD40 stimulation of resting peripheral blood B cells in the absence of IL-4 fails to induce any significant NF-{kappa}B activation implies that NF-{kappa}B itself is not involved in the CD40-mediated rescue of B cells from anti-IgM-induced apoptosis. Berberich et al. (14) demonstrated that anti-CD40 Ab alone was able to induce NF-{kappa}B DNA binding activity in purified tonsillar human B cells. More recently, Hess et al. (44) found that anti-CD40 Ab induced NF-{kappa}B mobilization in nonhemopoietic cells. One possible explanation for the differences between these results and those we describe here is that while our studies were performed with resting peripheral blood human B cells, the other groups used other sources of cells, activated or cycling to various degrees.

Our results suggest that NF-{kappa}B and IL-6 are intermediaries in sequential signaling pathways activated through both CD40 and IL-4 receptors in human B cells, leading to IgE production and secretion. Warren and Berton found that stimulation of murine B cells using a membrane-bound version of the CD40 ligand leads to detectable germline {epsilon} transcription (45). This induction appeared to be independent of the effects of other cytokines, most notably IL-4. Furthermore, stimulation with CD40 ligand and IL-4 together had a significant synergistic effect on germline {epsilon} transcription. The observed synergism between CD40 and IL-4 receptor signaling is not surprising given the demonstrated triggering of independent pathways by these receptors. IL-4R stimulation has been shown to lead to the induction of specific transcription factors, particularly STAT6 (46, 47). In contrast, CD40 has been shown to activate the c-Jun kinase pathway (9). The convergence point appears to lie upstream of NF-{kappa}B activation and may occur at the step of inactivation of I{kappa}B, the natural inhibitor of NF-{kappa}B. Recently, Iciek and co-workers found that nuclear complexes composed of both STAT6 and NF-{kappa}B proteins were induced synergistically by CD40 and IL-4 receptor stimulation (48). Furthermore, these complexes bound to a region of the germline {epsilon} promoter required for mediation of the synergistic effects of CD40 and IL-4 receptor stimulation on germline {epsilon} transcription. Cumulatively, these observations support the idea that CD40 and the IL-4 receptor activate pathways with distinct yet synergistic effects on IgE production.


   Acknowledgments
 
We thank Diane Nabighian for preparation of this manuscript.


   Footnotes
 
1 This work was supported in part by Grant HL36577 (to E.W.G.) from the National Institutes of Health. Back

2 Address correspondence and reprint requests to Dr. Erwin W. Gelfand, National Jewish Medical and Research Center, Denver, CO 80206. Back

3 Abbreviation used in this paper: AP-1, activating protein-1. Back

Received for publication August 5, 1996. Accepted for publication April 15, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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