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Mouse splenic B lymphocyte activation using different activation stimuli induces in vitro splicing of tumor necrosis factor-alpha nuclear pre-mRNA.
- Source :
-
Molecular immunology [Mol Immunol] 2006 Feb; Vol. 43 (6), pp. 613-22. - Publication Year :
- 2006
-
Abstract
- The pleiotropic functions of tumor necrosis factor-alpha (TNFalpha) have brought considerable attention in the past decade to its physiological and pathological roles in inflammatory and autoimmune diseases. However, little is known about how the production of TNFalpha is regulated at the transcriptional and translational levels in immune cells such as T and B lymphocytes. Our previous study demonstrated that unspliced "pre-mRNA" of TNFalpha is present in resting T cells. Initiation of splicing of TNFalpha pre-mRNA to mature mRNA requires T cell activation, which is unique and necessary for TNFalpha production when compared to its production in mononuclear phagocytes, including different lineages of macrophages (Mvarphi) and dendritic cells (DC). In this study, we further demonstrate that resting mouse B cells also contain pre-existing TNFalpha mRNA. The physiological process of B cell activation induced by (1) either the cross-linking of the B cell receptor (BCR) or CD40, (2) treatment with LPS, or PMA plus ionomycin, induces TNFalpha mRNA splicing in vitro. The kinetic response of TNFalpha splicing in B cells is much slower when compared to that in activated T cells. Studies using well-known kinase inhibitors demonstrated that MAP kinase kinase (MEK) and protein kinase C (PKC) are required for TNFalpha splicing upon stimulation through the BCR. These studies demonstrate that the production of TNFalpha in activated B cells is regulated differently than in activated T cells, and these differences may allow for the selective inhibition of TNFalpha in various autoimmune diseases depending on the mechanism of action of the selected anti-TNFalpha therapy.
- Subjects :
- Animals
B-Lymphocytes metabolism
Cell Nucleus
Lymphocyte Activation drug effects
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mitogen-Activated Protein Kinase Kinases
Protein Kinase C
Receptors, Antigen, B-Cell
Spleen immunology
T-Lymphocytes metabolism
Tumor Necrosis Factor-alpha biosynthesis
B-Lymphocytes immunology
Lymphocyte Activation immunology
RNA Precursors genetics
RNA Splicing immunology
Tumor Necrosis Factor-alpha genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0161-5890
- Volume :
- 43
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular immunology
- Publication Type :
- Academic Journal
- Accession number :
- 15899518
- Full Text :
- https://doi.org/10.1016/j.molimm.2005.04.010