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.
Copyright © 2007, Kristen K. Comfort
North Carolina State University
Place of Publication
Comfort, Kristen K., "Signaling Pathways Activated by Interleukin-2 and Interluekin-4 Receptors Mediate T Lymphocyte Clonal Expansion" (2007). Chemical and Materials Engineering Faculty Publications. 2.