IL-4 AND IFN-GAMMA SYNERGISTICALLY INCREASE TOTAL POLYMERIC IGA RECEPTOR LEVELS IN HUMAN INTESTINAL EPITHELIAL-CELLS - ROLE OF PROTEIN-TYROSINE KINASES

IL-4 and IFN-gamma increase release of secretory component (SC), the p olymeric IgA (pIgA)-binding segment of the pIgA receptor (pIgAR), by t he human intestinal epithelial cell line HT29. Moreover, these two cyt okines synergistically increase pIgA binding and cell surface staining for the receptor. To understand better the mechanism by which these c ytokines regulate pIgAR, we did quantitative immunoblotting using Abs against secretory component. We found that synergy occurs at the level of total cellular pIgAR. 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. C onversely, if cytokines were removed, then cellular pIgAR levels decre ased with an approximate t(1/2) of 20 h. Finally, synergy required the simultaneous presence of both cytokines throughout the treatment peri od, Direct measurement of second messengers and inhibitor studies sugg est that Ca2+, cAMP, protein kinase A, and protein kinase C do not pla y major roles in regulating cellular pIgAR levels by either cytokine, and do not contribute to the mechanism of synergy, In contrast, protei n tyrosine kinase inhibitors potently inhibited all cytokine-dependent increases in total cellular pIgAR. These results suggest that IL-4 an d IFN-gamma increase cellular pIgAR levels in HT29 cells predominantly by activating protein tyrosine kinase-dependent signaling pathways.