Document Type

Dissertation

Publication Date

10-2007

Abstract

Cells sense and respond to chemical and physical stimuli through signal transduction pathways, which mediate cell proliferation, differentiation, migration, and survival. The cytokines interleukin-2 (IL-2) and interleukin-4 (IL-4) are key regulators of the adaptive immune system, particularly influencing the clonal expansion and differentiation of T cells. At least in culture, both synergistic and antagonistic effects of IL-2 and IL-4 co-stimulation have been reported; the antagonism, when observed, is thought to arise from the utilization of a common subunit shared by IL-2 and IL-4 receptors. We have sought to characterize IL-2 and IL-4 signaling at the level of intracellular pathways activated by these receptors. IL-2 receptors are known to activate the Ras/extracellular signal-regulated kinase (Erk) and phosphoinositide (PI) 3-kinase/Akt pathways as well as the STAT5 transcription factor. IL-4 is unique among cytokines in that it does not activate Ras/Erk; it does activate PI 3-kinase/Akt as well as a distinct STAT, STAT6.

The HT-2 mouse T cell line responds to both IL-2 and IL-4. We found that IL-4 initially antagonizes, and later synergizes with, IL-2-stimulated HT-2 cell proliferation in a dose-dependent manner. Additionally, transient signaling through the PI3K/Akt and Ras/Erk pathways are required for optimal T cell proliferation. IL-4 stimulates cell adhesion in static cultures, again in a dose-dependent fashion, and it partially inhibits IL-2-stimulated activation of Akt, Erk and STAT5, consistent with a competition effect. IL-2/IL-4 co-stimulation provokes transient activation of Akt, Erk and STAT5 coupled with prolonged activation of STAT6. This signaling profile and the cell adhesion response suggest potential mechanisms by which IL-4 influences the proliferation of helper T cells.

Inclusive pages

1-96

Document Version

Published Version

Comments

Document is made available for download with the author's permission. Permission documentation is on file.

Publisher

North Carolina State University

Place of Publication

Raleigh, NC

Peer Reviewed

yes