Physiological and receptor-selective retinoids modulate interferon gamma signaling by increasing the expression, nuclear localization, and functional activity of interferon regulatory factor-1.
Synergistic actions between all-trans-retinoic acid (atRA) and interferon gamma (IFNgamma) on modulation of cellular functions have been reported both in vitro and in vivo. However, the mechanism of atRA-mediated regulation of IFNgamma signaling is poorly understood. In this study, we have used the human lung epithelial cell line A549 to examine the effect of atRA on IFNgamma-induced expression of IFN regulatory factor-1 (IRF-1), an important transcription factor involved in cell growth and apoptosis, differentiation, and antiviral and antibacterial immune responses. At least 4 h of pretreatment with atRA followed by suboptimal concentrations of IFNgamma induced a faster, higher, and more stable expression of IRF-1 than IFNgamma alone. Actinomycin D completely blocked the induction of IRF-1 by the combination, suggesting regulation at the transcriptional level. Further, we found that activation of signal transducer and activator of transcription-1 was induced more dramatically by atRA and IFNgamma than by IFNgamma alone. Expression of IFNgamma receptor-1 on the cell surface was also increased upon atRA pretreatment. Experiments using receptor-selective retinoids revealed that ligands for retinoic acid receptor-alpha (RARalpha), including atRA, 9-cis-retinoic acid, and Am580, sequentially increased the levels of IFNgamma receptor-1, activated signal transducer and activator of transcription-1, and IRF-1 and that an RARalpha antagonist was able to inhibit the effects of atRA and Am580. In addition, atRA pretreatment affected the transcriptional functions of IFNgamma-induced IRF-1, increasing its nuclear localization and DNA binding activity as well as the transcript levels of IRF-1 target genes. These results suggest that atRA, an RARalpha ligand, regulates IFNgamma-induced IRF-1 by affecting multiple components of the IFNgamma signaling pathway, from the plasma membrane to the nuclear transcription factors.
Luo
Xin M
XM
Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Ross
A Catharine
AC
D021581:Active Transport, Cell Nucleus; D000704:Analysis of Variance; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D015233:Models, Statistical; D010766:Phosphorylation; D011485:Protein Binding; D017471:Receptors, Interferon / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D000096743:Interferon gamma Receptor
D051017:Apoptosis Regulatory Proteins; D020170:Caspase 1; D004247:DNA; D003609:Dactinomycin; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D008024:Ligands; D008562:Membrane Glycoproteins; D017471:Receptors, Interferon; D012176:Retinoids; D050794:STAT1 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014212:Tretinoin; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C505653:TNFSF10 protein, human