Biomedical subjects

A Tsytsykova

Publications and source records attributed to A Tsytsykova.

3 recordsLinked to original sources

PubMed1998

CD40 ligation and IL-4 use different mechanisms of transcriptional activation of the human lymphotoxin alpha promoter in B cells.

We have previously shown that both CD40 ligation and IL-4 induce lymphotoxin alpha (LT alpha) expression in B cells. We generated a series of truncations of the LT alpha upstream region (-915 to +7 bp) and examined their ability to drive expression of a luciferase (LUC) reporter gene in B cells. The CD40-responsive promoter region of LT alpha was mapped to the region spanning -120 to -52 bp. This region contains an NF-kappa B site (-99 to -89 bp) which was shown to form a complex with nucleoproteins from CD40-stimulated B cells that contained the p50/p65 subunits of NF-kappa B. Mutation of the NF-kappa B site within the -356 to +7 bp region of the LT alpha gene completely abolished its capacity to drive transcription of the LUC gene in response to stimulation with CD40, but not to IL-4. The IL-4-responsive promoter region of LT alpha was mapped to the region spanning -265 to -185 bp. This region contains a site for binding to signal transducers and activators of transcription (STAT) proteins (-197 to -189 bp). This site was shown to form a complex with nucleoproteins from IL-4-stimulated B cells that contained STAT6. Mutation of the STAT site within the -356 to +7 bp region of the LT alpha gene completely abolished its capacity to drive transcription of the LUC gene in response to IL-4, but not to anti-CD40. These results demonstrate that CD40 and IL-4 use distinct mechanisms, namely activation of NF-kappa B and STAT6, respectively, to activate transcription of the LT alpha gene in B cells.

CD40 Antigens↗

PubMed1997

Homodimerization of the human interleukin 4 receptor alpha chain induces Cepsilon germline transcripts in B cells in the absence of the interleukin 2 receptor gamma chain.

The cytokines interleukin (IL)-4 and IL-13 play a critical role in inducing Cepsilon germline transcripts and IgE isotype switching in human B cells. The IL-4 receptor (IL-4R) in B cells is composed of two chains, the IL-4-binding IL-4Ralpha chain, which is shared with the IL-13R, and the IL-2Rgamma (gammac) chain, which is shared with IL-7R, IL-9R, and IL-15R. IL-4 induces Cepsilon germline transcripts and IgE isotype switching in B cells from patients with gammac chain deficiency. Induction of Cepsilon germline transcripts by IL-4 in B cells that lack the gammac chain may involve signaling via the IL-13R. Alternatively, the IL-4Ralpha chain may transduce intracellular signals that lead to Cepsilon gene transcription independently of its association with other chains. We show that ligand-induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 (Jak1) activation, STAT6 activation, and Cepsilon germline transcripts in human B cell line BJAB. Disruption of the Jak1-binding proline-rich Box1 region of IL-4Ralpha abolished signaling by this chimeric receptor. Furthermore, B cells transfected with a chimeric CD8alpha/IL-4Ralpha receptor, which is expressed on the cell surface as a homodimer, constitutively expressed Cepsilon germline transcripts. These results suggest that homodimerization of the IL-4Ralpha chain is sufficient to transduce Jak1-dependent intracellular signals that lead to IgE isotype switching.

Animals↗

PubMedDate not supplied

CD40 ligand/CD40 deficiency.

CD40 is a surface antigen expressed on B cells. The CD40 ligand (CD40L) is expressed on activated T cells. Interaction between CD40 and CD40L is critical for proliferation and isotype switching in the context of a response to a T-cell-dependent antigen. Patients with X-linked hyper-IgM syndrome (HIGMX-1) in their CD40L gene are unable to switch from IgM to IgG, IgA and IgE. Mice with a disrupted CD40 gene fail to undergo isotype switching to T-cell-dependent antigens but respond normally to T-independent antigens.

Animals↗