Lipopolysaccharide and dexamethasone induce mouse mammary tumor proviral gene expression and differentiation in B lymphocytes through distinct regulatory pathways.

Abstract

Endogenous mouse mammary tumor virus (MMTV) proviral transcripts are up regulated during the normal course of B-lymphocyte differentiation. We report here that the regulatory mechanisms which lead to increased levels of MMTV transcripts in differentiating, lipopolysaccharide (LPS)-stimulated normal B cells and in the inducible B-cell lymphoma line CH12 are at least partially distinct from those controlling increases in immunoglobulin and J-chain gene expression. In studies designed to characterize the stimulatory pathways leading to MMTV expression in CH12 cells, we found that stimulation with either LPS or dexamethasone (Dex), a transcriptional activator of MMTV genes, induced not only MMTV expression but also differentiation to antibody secretion. Only Dex-induced and not LPS-induced MMTV expression and differentiation were inhibited by the glucocorticoid antagonist RU486, demonstrating that Dex and LPS stimulate B cells by distinct molecular pathways. Therefore, in B cells, MMTV expression can be regulated via either the conventional hormone receptor-dependent pathway or a hormone receptor-independent pathway. Furthermore, these results suggest that steroid stimulation of B cells can lead to alterations in the expression of other steroid-responsive genes that can become involved in the process of B-cell differentiation.The stimulation of B lymphocytes results in the replication and differentiation of the responding subset into cells that secrete antibodies at a high rate. An understanding of the signal transduction pathways that are involved in the early stages of antigen-specific and mitogen-induced B-cell activation is emerging (reviewed in references 16 and 33), and the molecular events which regulate the increased steady-state expression of immunoglobulin and immunoglobulin-associated J-chain genes, known to be important to the differentiation process, are being characterized (9,11,37,46). Despite advances in these areas, however, the molecular events that are responsible for the differentiation of B cells into antibody-secreting cells remain ill defined. We have approached this problem by identifying and characterizing non-immunoglobulin gene products that are present in higher abundance in differentiating, antibody-secreting cells than in proliferating, non-antibody-secreting cells. We reasoned that an analysis of the molecular events which regulate the inducible expression of such gene products coupled with an understanding of their function should facilitate our understanding of the B-cell differentiation process.Using subtraction analysis, we recently identified a nonimmunoglobulin gene transcript that is expressed in higher abundance in lipopolysaccharide (LPS)-stimulated murine B cells than in unstimulated cells (54). Restriction mapping and sequence analysis of the gene product expressed in the inducible B-cell lymphoma line CH12 revealed that it was encoded by an endogenous mouse mammary tumor virus (MMTV) proviral locus, Mtv-9 (55). Although the cell surface expression of proteins which cross-re...

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“…It is known that other endogenous retroviruses, including porcine endogenous retroviruses (PERV), murine leukemia virus (MLV), and MMTV, exhibit increased expression after treatment with mitogens or immune-activating agents (63)(64)(65)(66). Although we did not see a difference in HML-2 upregulation between patients on or off antiretroviral therapy (Fig.…”

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“…7). (25). However, the putative enhancers, transcription factors, and binding sites involved are still elusive.…”

Homeoproteins CDP and SATB1 Interact: Potential for Tissue-Specific Regulation

“…Alternatively, other cell types may have nearly equimolar amounts of SATB1 and CDP, and these cells may have little repressor activity for the MMTV promoter from either CDP or SATB1. B cells may represent such a cell type, since they are relatively permissive for MMTV expression (23,50).…”