Induction of germ‐line immunoglobulin heavy chain transcripts by mitogens and interleukins prior to switch recombination

Severinson, Eva; Fernández, Carmen; Stavnezer, Janet

doi:10.1002/eji.1830200520

Cited by 108 publications

(50 citation statements)

References 51 publications

(49 reference statements)

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“…The class switching event is regulated by CD40-and IL-4R-induced NF-B and STAT-6 binding to the germline ␥1 promoter, respectively, to activate transcription of germline ␥1 (referred to as intervening ␥1 (I␥1)) (33)(34)(35)(36)(37)(38)(39). The production of mature IgG1 transcript is regulated by an increase in Oct coactivator from B cells (OCA-B) expression following CD40 stimulation to regulate the activity of the 3Ј IgH enhancer (40).…”

Section: Selective Regulation Of Mature Igg1 Transcription By Cd86mentioning

confidence: 99%

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Podojil

Sanders

2003

The Journal of Immunology

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Stimulation of CD86 and the β2-adrenergic receptor (β2AR) on a B cell, either alone or together, is known to increase the level of IgG1 protein produced by a CD40 ligand/IL-4-activated B cell. It is also known that the mechanism by which CD40 and IL-4R stimulation on a B cell increases the level of IgG1 protein is by increasing germline γ1 transcription, IgG1 class switching, and mature IgG1 transcription, while the molecular mechanism responsible for mediating the CD86- and β2AR-induced effect remains unknown. In the present study using real-time PCR we show that the level of mature IgG1 transcription increases in CD40 ligand/IL-4-activated B cells following stimulation of either CD86 and/or β2AR, and that this increase reflects the increase in IgG1 protein. Furthermore, we show that the CD86- and/or β2AR-induced increase in mature IgG1 transcript is due to an increase in the rate of mature IgG1 transcription, as determined by nuclear run-on analysis. This effect is additive when both receptors are stimulated and is lost when B cells from CD86- and β2AR-deficient mice are used. In contrast, the level of germline γ1 transcription, the stability of mature IgG1 transcript, the number of IgG1-positive B cells, and the number of IgG1-secreting B cells did not change. These results provide the first evidence that CD86 and/or β2AR stimulation on a CD40 ligand/IL-4-activated B cell increases the level of IgG1 protein produced per cell by increasing the rate of mature IgG1 transcription.

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Section: Selective Regulation Of Mature Igg1 Transcription By Cd86mentioning

confidence: 99%

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Podojil

Sanders

2003

The Journal of Immunology

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“…IL-4 directs class switch recombination to IgG1 and IgE by inducing GL ␥1 and ⑀ transcripts in activated B cells (25)(26)(27). CD40L or Ab to CD40 synergizes with IL-4 to further induce GL ⑀ and mouse ␥1 transcripts in cultured mouse splenic B cells (28 -32).…”

Section: U Pon Activation By Ag or Mitogens Igmmentioning

confidence: 99%

“…Previous reports indicate that the mouse GL ␥1 and ⑀ transcripts, which are required to direct class switch recombination to a particular S region and thereby a particular C H gene, are differentially regulated (25,27,28). In this manuscript, we attempt to dissect the mechanism for this differential regulation by comparing the regulation of the promoters for GL ␥1 and ⑀ transcripts.…”

Section: Comparison Of the Gl ␥1 And ⑀ Promotersmentioning

confidence: 99%

Differential Regulation of Mouse Germline Ig γ1 and ε Promoters by IL-4 and CD40

Chunsheng

Stavnezer

2001

The Journal of Immunology

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Before Ig class switching, RNA transcription through the specific S regions undergoing recombination is induced by cytokines and other activators that induce and direct switching. The resulting germline (GL) transcripts are essential for switch recombination. To understand the differential regulation of mouse IgG1 and IgE, we compared the promoters for GL γ1 and ε transcripts. We addressed the question of why the promoter that regulates GL ε transcription is more responsive to IL-4 than the γ1 promoter and also why GL ε transcription is more dependent on IL-4 than is γ1 transcription. We found that the IL-4-responsive region of the GL ε promoter is more inducible than that of the γ1 promoter, although each promoter contains a binding site for the IL-4-inducible transcription factor Stat6, located immediately adjacent to a binding site for a basic region leucine zipper (bZip) family protein. However, the arrangement and sequences of the sites differ between the ε and γ1 promoters. The GL ε promoter binds Stat6 with a 10-fold higher affinity than does the γ1 promoter. Furthermore, the bZip elements of the two promoters bind different transcription factors, as the GL ε promoter binds and is activated by AP-1, whereas the γ1 promoter binds and is activated by activating transcription factor 2. C/EBPβ and C/EBPγ also bind the γ1 bZip element, although they inhibit rather than activate transcription. However, inhibition of promoter activity by C/EBPβ does not require the bZip element and may instead occur via inhibiting the activity of NF-κB.

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“…30,31) IL-12 also stimulates the production of IgG2a, presumably through induction of IFN-g from T cells and NK cells. 32) Switching to IgG1 and IgE antibodies is regulated by IL-4 and inhibited by IFN-g. 41) Thus, Th1 cells are involved in the differentiation of B lymphocytes and production of the IgG2a isotype.…”

Section: (1→6)-branched (1→3)-b-d-glucans (B-glucans) Frommentioning

confidence: 99%

Th1/Th2-Balancing Immunomodulating Activity of Gel-Forming (1.RAR.3)-.BETA.-Glucans from Fungi.

Suzuki

Adachi

Ohno

et al. 2001

Biological & Pharmaceutical Bulletin

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(1→6)-branched (1→3)-b-D-glucans (b-glucans) fromfungi are known to enhance various immunopharmacological activities such as antitumor activity.1) Some of them, including lentinan 2) and sonifilan (SPG), 3) have been used clinically for cancer therapy in Japan. We have been investigating various immunopharmacological effects of b-glucans, such as grifolan (GRN) from Grifola frondasa 4) and sclerotinia sclerotiorum glucan (SSG) 5) from Sclerotinia sclerotiorum IFO 9395, which were isolated originally by our group. GRN has a similar primary structure to SPG,4) but SSG consists of a b-(1→3)-polyglucose backbone with every second residue substituted with mono-glucosyl branches. 5,6) The ultrastructure of GRN and SSG is distinct from that of SPG.7) GRN and SSG contain a mixture of single and triple helix conformers, whereas SPG is composed of triple helixes only. 8,9) The molecular weight of a single chain of SPG is 15 kDa, which is much lower than those of GRN (50 kDa) and SSG (200 kDa). 5,6,10) Our accumulated data suggest that the molecular weight, degree of branching, number of substituents, as well as ultrastructure, including the presence of single and triple helixes, significantly affects the biological activities of b-glucans. [11][12][13][14] For instance, it was demonstrated that GRN and SSG could more markedly induce various activities of immunological cells such as cytotoxic T cells and macrophages than SPG, although the antitumor effects of these two glucans were similar to those of SPG.15) Using SPG and SPG-OH, which is a single helical conformer prepared by alkaline treatment of SPG, we also found previously that the biological activities of b-glucans, i.e. blood clearance, 16) reactivity of limulus factor G activation, 17) and NO synthesis in vivo 18) and in vitro, are strongly associated with their conformation. 8,19) However we do not yet know the details of activities of various b-glucans on helper T cell modulation.T cell responses have been divided in two subclasses, Th1and Th2, according to the profile of the lymphokines produced, i.e., IFN-g and IL-2 vs. IL-4, IL-5, and IL-10, respectively. 20) Evidence is accumulating that cytokines play a role during T helper cell differentiation. IL-4 has a direct effect on the induction of IL-4-producing Th2 cells 21) and IFN-g causes the preferential outgrowth of Th1. 22) In addition, IL-4 appears to inhibit the induction of Th1 cells in vitro and in vivo. 23,24) Antigen-presenting cells such as macrophages and dendritic cells also play a major role in T helper cell differentiation. IL-12 derived from antigen-presenting cells stimulates IFN-g production from T cells and NK cells, thereby favoring a Th1-pattern of response. 25,26) There is clear evidence that IL-12 can suppress IL-4 mRNA induction, both directly and indirectly, through induction of 28) In the antibody response, IgG2a responses are induced by IFNg and suppressed by IL-4. 29) IFN-g promotes isotype switching to IgG2a.30,31) IL-12 also stimulates the production of IgG2a, presumably through i...

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Induction of germ‐line immunoglobulin heavy chain transcripts by mitogens and interleukins prior to switch recombination

Cited by 108 publications

References 51 publications

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Differential Regulation of Mouse Germline Ig γ1 and ε Promoters by IL-4 and CD40

Th1/Th2-Balancing Immunomodulating Activity of Gel-Forming (1.RAR.3)-.BETA.-Glucans from Fungi.

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