Year: 2009
Type: article
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 cytokinemediated 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)-γ 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-4generated ROS, in turn, promote IL-4 receptor activation by oxidatively inactivating protein tyrosine phosphatase 1B (PTP1B) that physically associates vii 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 the magnitude of IL-4 receptor activation and signal transduction.
Author: Rikhia Chakraborty
Institution: Cleveland State University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W944398850