Document Type

Dissertation

Publication Date

2006

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 -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 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 -4. We found that IL-4 initially antagonizes, and later synergizes with, IL-2-stimulated HT-2 cell proliferation in a dose-dependent manner. IL-4 also stimulates cell adhesion in static cultures. At the level of intracellular signaling, IL-4 antagonizes IL-2-stimulated activation of Akt, possibly through competition for limiting amounts of common receptor subunit and/or PI 3-kinase. Because IL-4 alone does not promote any Erk activation, we were surprised to find that IL-4 enhances IL-2-stimulated activation of Erk. IL-2/IL-4 co-stimulation provokes transient activation of STAT5 and prolonged activation of STAT6. This extended STAT6 activation may be critical in the IL-2/IL-4 induced synergy in T cell growth. Currently, we are investigating the crosstalk between these pathways and their functional roles in IL-2 and IL-4-stimulated T cell responses.

Inclusive pages

1-78

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