Retinoic acid inhibits IL-6-dependent but not constitutive STAT3 activation in Epstein-Barr virus-immortalized B lymphocytes.
IL-6-mediated B-cell growth promotion is involved in the pathogenesis of EBV+ lymphoproliferative disorders of immunosuppressed patients. Since retinoic acid (RA) inhibits the proliferation of EBV-immortalized lymphoblastoid B-cell lines (LCLs), we have investigated the effects of RA on IL-6 signaling in these cells. RA down-regulated IL-6-receptor components with IL-6 agonist activity (membrane and soluble gp80) and increased the levels of soluble gp130, an IL-6 antagonist. These changes, however, were not related to the enhanced production of endogenous IL-6 induced by RA in LCLs. RA-induced modulation of IL-6 receptor components did not abolish IL-6-mediated phosphorylation of gp130, whereas JAK1 and STAT3 phosphorylation and activation induced by IL-6 were markedly inhibited. Overall, the effects of RA resulted in the induction of a complete resistance of LCLs to IL-6-mediated growth promotion. Conversely, RA did not inhibit the constitutive activation of JAK1, TYK2, STAT3 and ERK1/2, ruling out that the JAK/STAT and MAPK pathways may mediate the antiproliferative activity of RA. The finding that RA severely impairs IL-6-dependent signalings in LCLs and inhibits their growth despite the presence of constitutively active JAK/STAT and MAPK cascades provide additional support for a role of RA in the prevention and treatment of EBV-related lymphoproliferative disorders of immunosuppressed patients.
Zancai
Paola
P
Immunovirology and Biotherapy Unit, Department of Pre-clinical and Epidemiological Research, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, Aviano (PN), Italy.
Cariati
Roberta
R
Quaia
Michele
M
Guidoboni
Massimo
M
Rizzo
Silvana
S
Boiocchi
Mauro
M
Dolcetti
Riccardo
R
D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology; D053613:Janus Kinase 1; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D053613:Janus Kinase 1; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014212:Tretinoin; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C494086:STAT3 protein, human; C507904:JAK1 protein, human