IL-4 and IFN-gamma increase steady state levels of polymeric Ig receptor mRNA in human airway and intestinal epithelial cells.
Delivery of IgA to the mucosal surface occurs via transcytosis of polymeric IgA (pIgA) across the epithelium, a process mediated by the pIgR. Several factors increase pIgR expression in human epithelial cells, including IL-4 and IFN-gamma. Using an RNase protection assay, we found that IL-4 and IFN-gamma increase steady state levels of pIgR mRNA in both human intestinal (HT29) and airway (Calu-3) epithelial cells. Time course studies in HT29 clone 19A cells showed that with each cytokine alone and with both together: 1) there was a significant lag before mRNA levels increased; 2) maximal levels were not reached until 48-72 h after the addition of cytokines; 3) mRNA levels remained elevated in the continued presence of cytokines; and 4) addition of actinomycin D or removal of cytokines led to decreases in mRNA levels with a half-life of approximately 20-28 h. Cytokine-dependent increases in steady state levels of pIgR mRNA were inhibited by cycloheximide and by protein tyrosine kinase inhibitors but not by inhibitors of protein kinase C or cAMP-dependent protein kinase A. Both IFN-gamma and IL-4 increased expression of the inducible transcription factor IFN regulatory factor-1 (IRF-1), but levels of IRF-1 only weakly correlated with levels of pIgR mRNA, suggesting that additional transcription factors are required. These studies provide additional insights into the mechanisms by which cytokines regulate expression of the pIgR, a central player in mucosal immunity.
Ackermann
L W
LW
Infectious Diseases Research Laboratory, Veterans Affairs Medical Center, Department of Internal Medicine, University of Iowa, Iowa City 52242, USA.
Wollenweber
L A
LA
Denning
G M
GM
D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D019073:HT29 Cells / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D019056:Receptors, Polymeric Immunoglobulin / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019056:Receptors, Polymeric Immunoglobulin; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D003513:Cycloheximide; D011505:Protein-Tyrosine Kinases