B cell early response gene expression coupled to B cell receptor, CD40 and interleukin-4 receptor co-stimulation: evidence for a role of the egr-2/krox 20 transcription factor in B cell proliferation.
B lymphocytes are activated following antigen stimulation of the B cell receptor but require co-stimulation with accessory molecules provided by interleukin (IL)-4/CD40 ligand for cell cycle progression and proliferation. By analyzing a panel of 11 early response genes induced by cross-linking of surface immunoglobulin, we show that CD40 signaling alone induces only 2 genes, c-myc together with an anonymous gene, 3L3, and that these are distinct from the set of genes induced in response to IL-4. Co-stimulation with the proliferative combination of anti-mu, IL-4 + CD40 signaling led to a fourfold enhancement of egr-2/krox 20 expression over that seen with anti-mu alone. Egr-2 expression/activity was selectively inhibited by the immunosuppressive drug cyclosporin A, and antisense oligonucleotide blockade of Egr-2 activity elicited a dose-dependent inhibition of B cell proliferation. Taken together, these observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from each other, but that certain genes, exemplified by egr-2, may represent a point of convergence in the integration of different signaling pathways into the B cell proliferative response.
Newton
J S
JS
Division of Life Sciences, King's College London, GB.
Li
J
J
Ning
Z Q
ZQ
Schoendorf
D E
DE
Norton
J D
JD
Murphy
J J
JJ
D015703:Antigens, CD / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D019013:CD40 Antigens / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051767:Early Growth Response Protein 2; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D018123:Receptors, Interleukin / Q000502:physiology*; D019948:Receptors, Interleukin-4; D015398:Signal Transduction / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D015703:Antigens, CD; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; D016376:Oligonucleotides, Antisense; D011947:Receptors, Antigen, B-Cell; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D013873:Thionucleotides; D014157:Transcription Factors; D016572:Cyclosporine