RETRACTED: REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns.
In the classic view interleukin-13 (IL-13) binds to a heterodimer protein complex of the IL-13Ralpha1 and IL-4Ralpha chains and signals through a Janus kinase 1 (JAK1)-signal transducer and activator of transcription 6 (STAT6) mechanism. We recently reported that IL-13 also signals through the IL-13Ralpha2 chain initiating all three mitogen activated protein kinase (MAPK) pathways, and the relative expression of IL-13Ralpha1 and IL-13Ralpha2 modulates one another's transduction pathway. Therefore we investigated whether generation of reactive oxygen species (ROS) as second messengers may serve as a common nexus between these two pathways emanating from the individual IL-13 receptor chains in intestinal epithelial cells (IEC). IL-13 stimulates intracellular ROS synthesis within 5min via IL-13Ralpha1-JAK1-STAT6- and IL-13Ralpha2-MEK1/2-ERK1/2-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1). IL-13-induced ROS generation in turn positively regulates phosphorylation of ERK1/2 and STAT6, yielding a feed forward amplification loop. IL-13 also stimulates the stable, long-term gene expression of two other NADPH oxidases, NOX-4 and DUOX-2, which along with constitutive NOX-1, might facilitate elevated, continuous production of ROS in IL-13-activated IEC. The contribution of each signal transduction pathway initiated by IL-13 engagement to such biological functions as wound healing, inflammation, and apoptosis was mapped for representative, responsive genes. Distinct usage patterns were observed, demonstrating not only that IL-13 signal transduction through STAT6, MAPK, and ROS is regulated in both an antagonistic and cyclic fashion, but also that each pathway plays a specific role in modulating the wound healing and anti-apoptotic capabilities of the intestinal epithelium.
Mandal
Debasmita
D
Department of Pathology, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4952, United States.
Fu
Pingfu
P
Levine
Alan D
AD
D045744:Cell Line, Tumor; D000074623:Dual Oxidases; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053660:Receptors, Interleukin-13 / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015290:Second Messenger Systems
D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053663:Interleukin-13 Receptor alpha2 Subunit; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053660:Receptors, Interleukin-13; D050800:STAT6 Transcription Factor; D000074623:Dual Oxidases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human; C431515:DUOX2 protein, human; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases