Induction of the Igkappa 3' enhancer by distinct pathways can be inhibited by cross-linking of the CD40 receptor.
Upon treatment with lipopolysaccharide (LPS), primary B cells proliferate and differentiate into plasma cells with concomitant up-regulation of immunoglobulin (Ig) gene expression. Here we examine the role of the Igkappa 3' enhancer in this process using a kappa3'-enhancer-driven beta-globin reporter gene in transgenic mice. We find that LPS treatment up-regulates kappa3' enhancer activity as a function of differentiation rather than proliferation, since proliferation only (induced by cross-linking of CD40) is insufficient to activate the element, whilst differentiation with only limited proliferation (LPS + transforming growth factor-beta) does allow activation to occur. The Igkappa 3' enhancer is also induced by cross-linking of surface Ig and this signal can synergize with LPS activation, suggesting that distinct activation pathways are used. Nevertheless, both of these pathways can be inhibited by co-cross-linking of CD40. Thus Ig enhancers in the heavy and light chain loci are differentially regulated in response to CD40.
Meyer
K B
KB
The Wellcome/CRC Institute of Cancer and Developmental Biology and Department of Pathology, University of Cambridge, GB. kbm1000@mole.bio.cam.ac.uk
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D005803:Genes, Immunoglobulin; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D007148:Immunoglobulin mu-Chains / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects
D000945:Antigens, Differentiation, T-Lymphocyte; D019013:CD40 Antigens; D003432:Cross-Linking Reagents; D007145:Immunoglobulin kappa-Chains; D007148:Immunoglobulin mu-Chains; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D023201:CD40 Ligand