Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway.
BACKGROUND
Chronic inflammation in ulcerative colitis (UC) is a sizeable risk factor for colorectal cancer (CRC). Interleukin-13 (IL-13) is elevated in the UC mucosa and may induce dysregulated signaling in neighboring intestinal epithelial cells (IECs) and thus function as a tumorogenic cytokine.


METHODS
Expression of IL-13 receptor chains on IECs obtained from control or chronically inflamed mucosa and colonic tumors was quantified by flow cytometry and immunoblot. IL-13Ralpha1 and IL-13Ralpha2 expression was significantly increased on IEC from UC and CRC patients compared to control and Crohn's disease (CD) subjects. Purified IEC from these subjects and cell lines expressing varying ratios of IL-13Ralpha1 and IL-13Ralpha2 chains were stimulated with IL-13 in vitro to investigate by immunoblot the activation of the signal transducer and activator of transcription 6 (STAT6) and mitogen activated protein kinase (MAPK) signaling pathways.


RESULTS
Despite similarly elevated receptor expression in UC and CRC, IL-13 does not activate the STAT6 or MAPK pathways in UC, while in colonic tumors only the STAT6 pathway is activated. Using neutralizing antibodies and cell lines expressing a range of surface densities for IL-13Ralpha1 and IL-3Ralpha2, we demonstrate that IL-13Ralpha2 serves a dual role, initiating MAPK signaling at low concentrations and as an inhibitory, decoy receptor at high IL-13Ralpha2 to IL-13Ralpha1 ratios.


CONCLUSIONS
IL-13Ralpha2 is both a decoy receptor and induces MAPK signal transduction, depending on its relative expression and the local concentration of IL-13, which together modulate the balance and intensity of the signaling pathways initiated in UC and CRC.
Mandal
Debasmita
D
Department of Pathology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA.
Levine
Alan D
AD
D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D057134:Antibodies, Neutralizing; D016207:Cytokines; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053663:Interleukin-13 Receptor alpha2 Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020928:Mitogen-Activated Protein Kinases