title: IL-4 and IFN-gamma synergistically increase total polymeric IgA receptor levels in human intestinal epithelial cells. Role of protein tyrosine kinases.
abstract: IL-4 and IFN-gamma increase release of secretory component (SC), the polymeric IgA (plgA)-binding segment of the plgA receptor (plgAR), by the human intestinal epithelial cell line HT29. Moreover, these two cytokines synergistically increase plgA binding and cell surface staining for the receptor. To understand better the mechanism by which these cytokines regulate plgAR, we did quantitative immunoblotting using Abs against secretory component. We found that synergy occurs at the level of total cellular plgAR. Additionally, time course studies indicated that maximal receptor levels required >24-h incubation, that reaching maximal levels required at least 18 h of cytokine treatment, and that receptor levels remained elevated as long as cytokines were present. Conversely, if cytokines were removed, then cellular plgAR levels decreased with an approximate t1/2 of 20 h. Finally, synergy required the simultaneous presence of both cytokines throughout the treatment period. Direct measurement of second messengers and inhibitor studies suggest that Ca2+, cAMP, protein kinase A, and protein kinase C do not play major roles in regulating cellular plgAR levels by either cytokine, and do not contribute to the mechanism of synergy. In contrast, protein tyrosine kinase inhibitors potently inhibited all cytokine-dependent increases in total cellular plgAR. These results suggest that IL-4 and IFN-gamma increase cellular plgAR levels in HT29 cells predominantly by activating protein tyrosine kinase-dependent signaling pathways.
authors.affiliation: Infectious Diseases Research Laboratory, Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Denning
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000008:administration & dosage*; D015847:Interleukin-4 / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011961:Receptors, Fc / Q000378:metabolism*; D019056:Receptors, Polymeric Immunoglobulin / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C045281:IgA receptor; D011961:Receptors, Fc; D019056:Receptors, Polymeric Immunoglobulin; D015847:Interleukin-4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases