scholarly journals 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.

1993 ◽  
Vol 178 (6) ◽  
pp. 2213-2218 ◽  
Author(s):  
G Aversa ◽  
J Punnonen ◽  
B G Cocks ◽  
R de Waal Malefyt ◽  
F Vega ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Interleukin 4 ◽  
Mutant Protein ◽  
Mutant Form ◽  
Common Component ◽  
Ige Synthesis ◽  
Agonistic Activity

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.

Retinoic Acid Inhibits CD40 + Interleukin-4–Mediated IgE Production In Vitro

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1713-1720 ◽  
Author(s):  
M. Worm ◽  
J.M. Krah ◽  
R.A. Manz ◽  
B.M. Henz
Keyword(s):  
Retinoic Acid ◽  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Interleukin 4 ◽  
Dependent Manner ◽  
Maximal Inhibition ◽  
Ige Synthesis ◽  
Dose Dependent

Abstract To elucidate the role of retinoic acid (RA) in anti-CD40 + interleukin-4 (IL-4)–mediated B-cell activation, the effect of 10−12 to 10−6 mol/L RA was studied in anti-CD40 (1 μg/mL) + IL-4 (5 ng/mL)-mediated proliferation and Ig synthesis by human peripheral blood mononuclear cells (PBMC) and B cells in healthy donors. Anti-CD40 + IL-4–mediated proliferation of PBMC and B cells was inhibited by RA in a dose-dependent manner, with maximal inhibition of 62% ± 5% in PBMC and 55% ± 4.4% in B cells by all-trans RA, and 58% ± 6.7% and 51% ± 4.7%, respectively by 13-cis RA. IgE synthesis was even more markedly inhibited by RA starting at concentrations of >10−14mol/L for B cells and >10−10 mol/L for PBMC. Maximal inhibition of IgE production for B cells was at 10−8mol/L for all-trans RA (94% ± 1.8%) and 96% ± 3.2% for 13-cis RA. Low concentrations of RA inhibiting IgE synthesis (10−10 mol/L) affected neither B-cell proliferation nor the production of IgA, IgG, and IgM. Elucidation of the mechanism involved in this inhibition of IgE production shows that epsilon germline transcription is decreased by RA, whereas production of interferon-γ (IFN-γ) was not enhanced in the presence of RA. To differentiate whether the RA effect was mediated by RA receptors , β, and γ, the expression of the retinoic acid receptors (RAR) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The data show that unstimulated human peripheral B cells express mRNA of the RA receptor , β, and γ. Using retinoids with different receptor binding specificity (CD336, CD437, CD2019, CD367), dose-dependent inhibition of IgE synthesis was shown by all four derivates, but was most marked by an RA binding the  receptor with high specificity. Taken together, this study shows that RA inhibits IgE production of anti-CD40 + IL-4–stimulated B cells in vitro. © 1998 by The American Society of Hematology.

Retinoic Acid Inhibits CD40 + Interleukin-4–Mediated IgE Production In Vitro

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1713-1720 ◽  
Author(s):  
M. Worm ◽  
J.M. Krah ◽  
R.A. Manz ◽  
B.M. Henz
Keyword(s):  
Retinoic Acid ◽  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Interleukin 4 ◽  
Dependent Manner ◽  
Maximal Inhibition ◽  
Ige Synthesis ◽  
Dose Dependent

To elucidate the role of retinoic acid (RA) in anti-CD40 + interleukin-4 (IL-4)–mediated B-cell activation, the effect of 10−12 to 10−6 mol/L RA was studied in anti-CD40 (1 μg/mL) + IL-4 (5 ng/mL)-mediated proliferation and Ig synthesis by human peripheral blood mononuclear cells (PBMC) and B cells in healthy donors. Anti-CD40 + IL-4–mediated proliferation of PBMC and B cells was inhibited by RA in a dose-dependent manner, with maximal inhibition of 62% ± 5% in PBMC and 55% ± 4.4% in B cells by all-trans RA, and 58% ± 6.7% and 51% ± 4.7%, respectively by 13-cis RA. IgE synthesis was even more markedly inhibited by RA starting at concentrations of >10−14mol/L for B cells and >10−10 mol/L for PBMC. Maximal inhibition of IgE production for B cells was at 10−8mol/L for all-trans RA (94% ± 1.8%) and 96% ± 3.2% for 13-cis RA. Low concentrations of RA inhibiting IgE synthesis (10−10 mol/L) affected neither B-cell proliferation nor the production of IgA, IgG, and IgM. Elucidation of the mechanism involved in this inhibition of IgE production shows that epsilon germline transcription is decreased by RA, whereas production of interferon-γ (IFN-γ) was not enhanced in the presence of RA. To differentiate whether the RA effect was mediated by RA receptors , β, and γ, the expression of the retinoic acid receptors (RAR) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The data show that unstimulated human peripheral B cells express mRNA of the RA receptor , β, and γ. Using retinoids with different receptor binding specificity (CD336, CD437, CD2019, CD367), dose-dependent inhibition of IgE synthesis was shown by all four derivates, but was most marked by an RA binding the  receptor with high specificity. Taken together, this study shows that RA inhibits IgE production of anti-CD40 + IL-4–stimulated B cells in vitro. © 1998 by The American Society of Hematology.

scholarly journals Role for low-affinity receptor for IgE (CD23) in normal and leukemic B- cell proliferation

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1881-1886 ◽  
Author(s):  
S Fournier ◽  
M Rubio ◽  
G Delespesse ◽  
M Sarfati
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Early Stage ◽  
Lymphocytic Leukemia ◽  
Interleukin 4 ◽  
B Cell Activation ◽  
Type B ◽  
Cd23 Expression

Abstract CD23 gene is overexpressed and abnormally regulated in the most frequent adult leukemic disorder, B chronic lymphocytic leukemia (B- CLL). Switch on and off in the upregulation of surface CD23 expression consistently occurs in the early stage of normal B-cell activation, suggesting a key role for CD23 in this process. We show here that, after ligation of mlg in the presence of interleukin-4, the increase of CD23 protein precedes B-cell DNA synthesis and mainly results from the strong induction of CD23 type-B isoform. Exposure of normal B cells to conventional or phosphorothioate-derivatized CD23 antisense oligonucleotides (predominantly type B) significantly augments B-cell proliferation induced by antigen receptor stimulation or direct contact with activated T cells. Unexpectedly, CD23 antisense, but not sense, oligonucleotides specifically enhance rather than suppress CD23 expression on B cells. Finally, a selective increase in CD23 type-B expression provokes the entry of resting (Go) CLL B cells into G1 and S phase of the cell cycle in the absence of any other stimulus, whereas it synergizes with tumor necrosis factor-alpha to increase the number of activated B cells. These results provide compelling evidence that CD23 represents an important molecule directly involved in the process of normal or leukemic B-cell activation and growth.

scholarly journals Interleukin 4 inhibits the proliferation but not the differentiation of activated human B cells in response to interleukin 2.

1988 ◽  
Vol 168 (4) ◽  
pp. 1321-1337 ◽  
Author(s):  
T Defrance ◽  
B Vanbervliet ◽  
J P Aubry ◽  
J Banchereau
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Tritiated Thymidine ◽  
Interleukin 2 ◽  
Optimal Concentration ◽  
Interleukin 4 ◽  
Aureus Strain ◽  
Igm Antibody

The combined effect of IL-4 and IL-2 on proliferation of anti-IgM antibody or Staphylococcus aureus strain Cowan I (SAC)-preactivated B cells was investigated. It was observed that in most cases, rIL-2 used at optimal concentration induced higher levels of tritiated thymidine ([3H]TdR) uptake than rIL-4 used at optimal concentration. When rIL-4 and rIL-2 were added together, it was repeatedly found that B cell proliferation induced by rIL-2 was significantly reduced and was, in most cases, comparable with the proliferation induced by rIL-4 alone. Cell cycle studies demonstrated that rIL-4 significantly reduced the number of cells entering S and G2/M phases of the cell cycle upon rIL-2 stimulation. B cell blasts preincubated for 24 or 48 h with rIL-4 displayed a reduced proliferation in response to rIL-2. In contrast, preculture of resting B cells with rIL-4 did not impair their subsequent proliferation in response to rIL-2 plus insolubilized anti-IgM antibody. This suggests that rIL-4 can only exert its inhibitory effect once B cells have received an activation signal. The differentiative activity of rIL-2 measured on B cell blasts preactivated for 2 d with SAC was not altered by rIL-4, which suggests that rIL-4 did not exert its inhibitory activity on rIL-2-induced B cell proliferation by enhancing rIL-2-mediated differentiation. Delayed addition of a neutralizing anti-IL-4 antiserum demonstrated that a period of contact of at least 24 h between IL-4 and B cell blasts was necessary for the development of the antagonistic effect of IL-4 on IL-2-mediated growth of activated B cells. These data demonstrate that IL-4 antagonizes the B cell growth-promoting effect of IL-2 without affecting the differentiation of preactivated B cells in response to IL-2.

scholarly journals Disodium cromoglycate inhibits S mu-->S epsilon deletional switch recombination and IgE synthesis in human B cells.

1994 ◽  
Vol 180 (2) ◽  
pp. 663-671 ◽  
Author(s):  
R K Loh ◽  
H H Jabara ◽  
R S Geha
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Allergic Disease ◽  
Interleukin 4 ◽  
Pokeweed Mitogen ◽  
Disodium Cromoglycate ◽  
Isotype Switching ◽  
Human B Cells ◽  
Ige Synthesis

IgE synthesis requires interleukin 4 (IL-4) and a T-B cell interaction that involves the B cell antigen CD40 and its ligand expressed on activated T cells. IL-4 induces epsilon germline transcription whereas ligation of CD40 results in deletional S mu-->S epsilon switch recombination, expression of mature epsilon transcripts, and IgE synthesis and secretion. We demonstrate that disodium cromoglycate (DSCG), a drug commonly used for the prophylactic treatment of allergic disease, inhibits T cell-driven IgE synthesis by human B cells at concentrations readily achievable in the course of inhaled therapy for asthma. Inhibition of IgE synthesis by DSCG was not the result of drug toxicity because DSCG did not affect the viability of T and B cells or their proliferation to mitogens. DSCG did not interfere with CD40 ligand expression by T cells but clearly targeted the B cells because it inhibited IgE synthesis induced by anti-CD40 and IL-4 in populations of highly purified B cells. DSCG had no effect on the induction of epsilon germline transcripts by IL-4 but strongly inhibited CD40 mediated S mu-->S epsilon deletional switch recombination in IL-4-treated B cells as assayed by nested primer PCR. The effect of DSCG was not specific for CD40-mediated induction of IgE isotype switching because DSCG inhibited IgE synthesis as well as S mu-->S epsilon deletional switch recombination induced by hydrocortisone and IL-4 in B cells. Moreover, the effect of DSCG was not specific for IgE isotype switching because DSCG inhibited the synthesis of IgG4 by B cells sorted for lack of surface expression of IgG4 and stimulated with anti-CD40 and IL-4. DSCG caused only minimal inhibition (< 15%) of spontaneous IgE synthesis by lymphocytes from patients with the hyper-IgE syndrome and did not affect pokeweed mitogen-induced IgG and IgA synthesis by lymphocytes suggesting that it has little effect on B cells that have already undergone isotype switching. These results indicate that DSCG inhibits switching to IgE in B cells and suggest a novel potential mechanism for the prevention of allergic disease by DSCG.

scholarly journals Role for low-affinity receptor for IgE (CD23) in normal and leukemic B- cell proliferation

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1881-1886
Author(s):  
S Fournier ◽  
M Rubio ◽  
G Delespesse ◽  
M Sarfati
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Early Stage ◽  
Lymphocytic Leukemia ◽  
Interleukin 4 ◽  
B Cell Activation ◽  
Type B ◽  
Cd23 Expression

CD23 gene is overexpressed and abnormally regulated in the most frequent adult leukemic disorder, B chronic lymphocytic leukemia (B- CLL). Switch on and off in the upregulation of surface CD23 expression consistently occurs in the early stage of normal B-cell activation, suggesting a key role for CD23 in this process. We show here that, after ligation of mlg in the presence of interleukin-4, the increase of CD23 protein precedes B-cell DNA synthesis and mainly results from the strong induction of CD23 type-B isoform. Exposure of normal B cells to conventional or phosphorothioate-derivatized CD23 antisense oligonucleotides (predominantly type B) significantly augments B-cell proliferation induced by antigen receptor stimulation or direct contact with activated T cells. Unexpectedly, CD23 antisense, but not sense, oligonucleotides specifically enhance rather than suppress CD23 expression on B cells. Finally, a selective increase in CD23 type-B expression provokes the entry of resting (Go) CLL B cells into G1 and S phase of the cell cycle in the absence of any other stimulus, whereas it synergizes with tumor necrosis factor-alpha to increase the number of activated B cells. These results provide compelling evidence that CD23 represents an important molecule directly involved in the process of normal or leukemic B-cell activation and growth.

scholarly journals The B cell-specific transcription factor BSAP regulates B cell proliferation.

1994 ◽  
Vol 179 (4) ◽  
pp. 1099-1108 ◽  
Author(s):  
Y Wakatsuki ◽  
M F Neurath ◽  
E E Max ◽  
W Strober
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Function ◽  
De Novo ◽  
Interleukin 4 ◽  
Cross Linking ◽  
Nuclear Extracts

The B cell-specific activator protein (BSAP) is a DNA-binding transcription factor expressed in pro-B, pre-B, and mature B cells, but not in plasma cells. In this study, we explored the role of BSAP in B cell function by assessing how the content of this protein varies in cells driven by proliferative stimuli and, conversely, how artificial manipulation of BSAP activity affects cell proliferation. We found that BSAP activity of nuclear extracts increased when B cells were activated by mitogen (lipopolysaccharide [LPS]), antigen receptor-mediated signaling (surface immunoglobulin D [IgD] cross-linking) or T cell-dependent stimulation (CD40 cross-linking). We could suppress BSAP activity by exposure of B cells to phosphorothioate oligonucleotides antisense to the BSAP translation initiation start site, whereas control oligonucleotides were virtually inactive. Antisense-induced BSAP suppression was associated with a striking reduction in LPS-induced proliferation of splenic B cells and in the spontaneous proliferation of B lymphoma cells (CH12.LX), but the antisense oligonucleotide had virtually no effect on proliferation of two cell lines lacking BSAP: the T lymphoma line EL-4 and the plasma cell line MOPC-315. Overexpression of BSAP in splenic B cells or de novo expression in MOPC-315 plasma cells induced by transfection of a BSAP expression plasmid stimulated cell proliferation. Taken together, these results suggest that BSAP activity is a rate-limiting regulator of B cell proliferation. We also found that treatment with the antisense BSAP oligonucleotide downregulated Ig class switching induced by interleukin 4 plus LPS. This effect may be secondary to reduced proliferation or could be mediated through BSAP binding sites in the IgH locus.

scholarly journals CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells.

1990 ◽  
Vol 172 (6) ◽  
pp. 1861-1864 ◽  
Author(s):  
H H Jabara ◽  
S M Fu ◽  
R S Geha ◽  
D Vercelli
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
B Cell Differentiation ◽  
Human B Cells ◽  
Molecular Events ◽  
Ige Synthesis ◽  
Ige Response

A novel pathway of IgE-B cell differentiation has been identified. Engagement of the B cell antigen CD40 by F(ab')2 fragments of monoclonal antibody (mAb) 626.1 in the presence of recombinant interleukin 4 (rIL-4) induced intense IgE synthesis, but modest IgG synthesis, by highly purified human B cells. Surface IgE- B cells isolated by cell sorting were induced to produce IgE by mAb 626.1 and IL-4. Thus, IgE synthesis is unlikely to result from expansion of a B cell population precommitted to IgE in vivo. A neutralizing anti-IL-6 antibody strongly, but not completely, inhibited the IgE response. This indicates that autocrine production of IL-6 plays an important amplification role in IgE synthesis triggered by anti-CD40 mAb and IL-4. Although the exact role played by CD40 in IgE responses in vivo remains to be established, this T cell-independent system represents a useful model to characterize the biochemical and molecular events leading to IgE synthesis in human B cells.

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