Interferon-gamma gene expression in human B-cell lines: induction by interleukin-2, protein kinase C activators, and possible effect of hypomethylation on gene regulation

Abstract

Human interferon-gamma (IFN-gamma) is an important immunomodulatory protein produced predominantly by T cells and large granular lymphocytes (LGLs). Whereas large amounts of data have been accumulated regarding IFN gamma gene expression in these two cell types, little information about IFN gamma expression in other cell types exists. In this study, we have analyzed the production of IFN gamma by the Epstein- Barr virus (EBV)-positive B-cell line, JLP(c), derived from a patient with Burkitt's lymphoma, and another human B-cell line, PA682BM-1, which was derived from an acquired immunodeficiency syndrome patient. Southern blot analysis indicates the presence of an Ig heavy chain gene rearrangement, but no rearrangement of the T-cell receptor beta chain gene or IFN gamma gene in these B-cell lines. Both cell lines were found to express surface IgD and other B-cell surface markers, thus confirming their B-cell lineage. Analysis for surface Ig, cytoplasmic Ig, and secreted Ig indicates that the two cell lines are in relatively early stages of the B-cell differentiation pathway. We now report that PA682BM-1 can be triggered by the protein kinase C (PKC) activators, phorbol 12-myristate 13-acetate (PMA) and (-)Indolactam-v, to secrete IFN gamma, whereas JLP(c) cells spontaneously produce low levels of IFN gamma that can be enhanced by PKC activators and interleukin-2 (IL-2). After activation of the cell lines with IL-2, (-)Indolactam-v, and PMA, increases in cytoplasmic messenger RNAs (mRNAs) of IFN gamma and the IL- 2 receptor chains were also observed. The induction of IFN gamma mRNA and protein by IL-2 was completely blocked by a monoclonal antibody to IL-2 receptor p75 (beta chain), but not by the monoclonal antibody to p55 (alpha chain). Analysis of IFN gamma genomic DNA indicates that the gene is not amplified, but that hypomethylation in the 5′ noncoding region of the IFN gamma gene has occurred in the B-cell line from the Burkitt's lymphoma patient that spontaneously produces IFN gamma. This finding suggests that the methylation state of the promoter region may play an important role in the control of IFN gamma gene expression in B cells.

Antigens Varying in Affinity for the B Cell Receptor Induce Differential B Lymphocyte Responses

“…3). B cells are reported to be capable of producing IL-2, IL-6, and IFN-␥ (44)(45)(46)(47)(48), but the ability of B cells to secrete IL-2 and IFN-␥ is not widely accepted. Only P31 and P5 were able to upregulate IL-2 and IFN-␥, whereas all of the 3-83-binding phage induced an increase IL-6 mRNA.…”

B cells modulate T cells so as to favour T helper type 1 and CD8+ T‐cell responses in the acute phase of Trypanosoma cruzi infection

“…In addition, it has being recognized that B cells produce a number of cytokines that might regulate function and/or survival of T cells. [14][15][16]55 Alternatively, it is possible that B cells influence the activity of other lymphoid or myeloid populations, 60,61 which could, in their turn, provide activation and/or survival signals for T cells. For instance, it was described that NK cells and Vc1-bearing cd T cells are involved in the generation of memory in the conventional T-cell compartment.…”

“…12,13 Besides that, it has being recognized that B cells may produce different cytokines upon stimulation, including interferon-c (IFN-c), interleukin (IL)-10 and IL-12. [14][15][16] Consequently, B cells may well contribute Fabiola Cardillo, 1 Edilberto Postol, 2 Jorge Nihei, 1 Luiz S. Aroeira, 3 Auro Nomizo 4 and José Mengel 1…”

Different signaling pathways inhibit DNA methylation activity and up-regulate IFN-γ in human lymphocytes

“…It is also of interest to note that human immunodeficiency virus type 1 infection of human T cells inhibits IFN-␥ gene expression associated with CpG hypermethylation in its promoter and that treatment of infected cells with an antisense DNA methyltransferase reverses the hypermethylation and increases IFN-␥ expression [26]. In addition, IFN-␥ production in vivo is regulated tightly, and PKC activity seems to be involved in the signal transduction leading to IFN-␥ gene transcription [27,28].…”