Date of Award

2009

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Haque, Saikh J.

Subject Headings

Interleukins, Active oxygen, NAD (Coenzyme), Oxidases, IL-4, ROS, NOX, Jak-STAT, Peroxiredoxins

Abstract

Cytokines are intracellular messengers that activate multiple signaling pathways and regulate cell survival, differentiation, migration, apoptosis and immune responses. We are investigating the homeostatic control of cytokine-mediated cell signaling using interleukin-4 (IL-4) as a model cytokine. Protein tyrosine phosphorylation is essential for cytokine-dependent signal transduction through the Janus Kinase-Signal Transducer and Activator of Transcription (Jak-STAT) pathway. Therefore, protein tyrosine dephosphorylation is a key mechanism providing the homeostatic control of the pathway. Here, we have shown for the first time that immediately following ligand-dependent activation, IL-4 receptor induces an intracellular calcium flux via insulin receptor substrate (IRS)-phosphoinositide 3-kinase (PI3K)-phospholipase C (PLC)-gamma pathway which, in turn, induces protein kinase C (PKC)-dependent activation of NAD(P)H oxidase (NOX)5 that generates reactive oxygen species (ROS). IL-4 also induces NOX1-mediated ROS production via IRS-PI3K-Ras-related C3 botulinum toxin substrate (RAC) 1 pathway. Moreover, we have also demonstrated that IL-4-generated ROS, in turn, promote IL-4 receptor activation by oxidatively inactivating protein tyrosine phosphatase 1B (PTP1B) that physically associates with and deactivates IL-4 receptor. In addition, we have shown that antioxidant enzymes peroxiredoxin II, IV and VI (Prx II, IV, VI) physically interact with the IL-4 receptor and become oxidized by IL-4 generated ROS, thereby neutralizing IL-4 generated ROS and compromising ROS-mediated amplification of IL-4 signaling. Cytokine-activated Jak-STAT pathway is believed to operate from cell surface to the nucleus via DNA-protein and protein-protein interactions without involving any second messengers. Here, we demonstrate, for the first time to our knowledge, a role for second messengers (ROS) in the amplification of Jak-STAT signal transduction in IL-4-stimulated cells. Further, our data suggests that redox status of cells controls th

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