Androgen dependent regulation of bacillus Calmette-Guerin induced interleukin-6 expression in human transitional carcinoma cell lines.
OBJECTIVE
Autocrine expression of interleukin (IL)-6 by transitional cell carcinoma (TCC) in response to bacillus Calmette-Guerin (BCG) may have an important role in promoting BCG adherence to TCC and consequently in BCG treatment efficacy. IL-6 expression in response to BCG requires nuclear factor (NF)-kappaB mediated signal transduction. We evaluated the influence of androgens on BCG induced, NF-kappaB mediated IL-6 expression.


METHODS
Reverse transcriptase-polymerase chain reaction was used to confirm androgen receptor expression in the human TCC lines 253J and T24. A reporter construct containing an androgen response element was used to establish the integrity of androgen mediated signal transduction. Subsequently the dose dependent effect of dihydrotestosterone (DHT) on BCG induced IL-6 expression and NF-kappaB signaling was evaluated. Two pharmacological androgen receptor blockers were used to determine if receptor blockade inhibited the effect of DHT on activation of the androgen response element, NF-kappaB signaling and BCG induced IL-6 expression.


RESULTS
The 2 human TCC lines expressed androgen receptor and demonstrated intact androgen stimulated signaling pathways. DHT suppressed BCG induced, NF-kappaB mediated signaling and IL-6 expression in a dose dependent manner. DHT decreased mRNA levels of IL-6, expression of the full-length IL-6 promoter construct and expression of an NF-kappaB specific reporter construct in response to BCG relative to controls. Competitive pharmacological blockade of androgen receptor inhibited the effect of DHT on BCG induced signaling in dose dependent fashion.


CONCLUSIONS
DHT down-regulates NF-kappaB mediated IL-6 expression by human TCC lines in response to BCG. This effect depends on a functional androgen receptor signaling pathway and it can be blocked by the inhibition of androgen/androgen receptor binding.
Chen
Fanghong
F
Department of Urology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA.
Langenstroer
Peter
P
Zhang
Guangjian
G
Iwamoto
Yoshiki
Y
See
William  A
W
D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000276:immunology; D001500:BCG Vaccine / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000276:immunology; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000276:immunology; D009570:Nitriles; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000276:immunology; D014613:Vaccines, Attenuated / Q000494:pharmacology
D000726:Androgen Antagonists; D000813:Anilides; D001500:BCG Vaccine; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D014105:Tosyl Compounds; D014613:Vaccines, Attenuated; D013196:Dihydrotestosterone; D005485:Flutamide; C053541:bicalutamide