TGF-beta1 suppresses IL-6-induced STAT3 activation through regulation of Jak2 expression in prostate epithelial cells.
Chronic inflammation plays an important role in the initiation and progression of various human diseases including benign prostatic hyperplasia or prostate cancer. Here we show that the proinflammatory cytokine interleukin-6 (IL-6) has prosurvival effects and chronically activates the Jak2/STAT3 signalling pathway in a model of benign prostatic hyperplasia (BPH-1). We demonstrate that the antiinflammatory cytokine transforming growth factor-beta1 (TGF-beta1), which also permanently activates its canonical signalling pathway through SMAD proteins in BPH-1 cells, modifies the effects of IL-6 on cell proliferation. Importantly, TGF-beta1 inhibits IL-6 signal transduction by decreasing the phosphorylation levels of STAT3. This effect is associated with decreased expression of Jak2 at both mRNA and protein levels. Moreover, we showed that TGF-beta1 inhibits IL-6-induced expression of the cancer-associated gene MUC1. These observations demonstrated a novel interaction between TGF-beta1 and IL-6 signalling and suggested another mechanism of how defects in TGF-beta signalling, frequently associated with prostate pathologies, can contribute to the disruption of tissue homeostasis.
Starsíchová
Andrea
A
Department of Cytokinetics, Institute of Biophysics, Acad Sci Czech Rep, Královopolská 135, CZ-612 65 Brno, Czech Republic.
Lincová
Eva
E
Pernicová
Zuzana
Z
Kozubík
Alois
A
Soucek
Karel
K
D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018396:Mucin-1 / Q000378:metabolism; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D015850:Interleukin-6; D053614:Janus Kinase 2; D018396:Mucin-1; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000093242:Interleukin-6 Inhibitors; C060192:MUC1 protein, human; C494086:STAT3 protein, human