Interleukin-4-mediated regulation of CD25 gene expression in human B lymphocytes

McKay, Catriona Elizabeth (1996) Interleukin-4-mediated regulation of CD25 gene expression in human B lymphocytes. PhD thesis, University of Glasgow.

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This thesis describes the regulation of CD25 gene expression by interleukin-4-activated signal transduction pathways in quiescent human B lymphocytes. In particular, the importance of a cAMP-dependent pathway, which down-regulates binding of a putative transcriptionally repressive protein factor from a negative regulatory element in the promoter region of the CD25 gene, is highlighted. CD25 is the alpha chain of the multi- component interleukin-2 receptor complex and is a requirement for formation of high affinity interleukin-2 receptors. In addition, CD25 is the only unique component of the interleukin-2 receptor and as such it confers rigourous specificity for binding of interleukin-2. To date, interleukui-4 is the only cytokine recognized to be capable of upregulating CD25 in human B lymphocytes. The initial aim of this work was to identify signalling pathways which were responsible for up-regulation of CD25 expression, by artificially activating specific second messenger systems. These early studies were based on the limited knowledge of interleukin-4-induced signal transduction pathways available at the time; treatment of resting human B cells with phorbol ester, calcium ionophore and forskolin results in modest increases in cell surface levels of CD25. Additionally, these stimuli and those required for elevation of surface CD23 levels are similar. It seemed possible therefore, that the ability of IL-4 to promote increases in intracellular calcium, protein kinase C activation and cAMP generation might have a role in IL-4-induced CD25 expression. Additionally, chelation of intracellular calcium and down-regulation of PKC, by chronic phorbol ester treatment, attenuates the ability of IL-4 to up-regulate CD25. Similarly, this latter treatment abrogates any increase in CD25 levels observed in response to anti-Iimmunoglobulin and anti-CD40 antibodies, the only other stimuli capable of inducing CD25 expression in primary human B cells. Upon binding to its receptor, IL-4 induces a biphasic elevation of intracellular cAMP; a transient increase which peaks at approximately 2 minutes and is followed by a more sustained increase after 10 minutes. This sustained cAMP generation is maintained until approximately 30 minutes after stimulation, before dropping back to basal levels. Additionally, we have demonstrated that IL-4-induced cAMP production is dose dependent and leads to the activation of the cAMP-dependent protein kinase, PKA, in primary human B cells. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Cushley, Dr. Wiliam
Date of Award: 1996
Depositing User: Enlighten Team
Unique ID: glathesis:1996-71654
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 13:58
Last Modified: 05 Jul 2022 15:39
Thesis DOI: 10.5525/gla.thesis.71654

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