Interleukin-4 in patients with prostate cancer.
BACKGROUND
Ligand-independent activation of the androgen receptor (AR) by cytokines has been implicated in the progression of androgen-independent prostate cancer (PCa). To determine the potential effects of elevated levels of interleukin-4 (IL-4) in patients with PCa, six different cytokines were examined for their ability to activate the AR.


METHODS
LNCaP cells were transiently transfected with prostate-specific antigen (PSA) (-630 / +12)-luciferase and treated with R1881, six kinds of cytokines including IL-4, or vehicle. Transactivation assays were also performed in LNCaP cells co-transfected with the 5xGal4UAS-TATA-luciferase and AR-(1-558)-Gal4DBD prior to incubation with R1881, IL-4, IL-6, or vehicle. Seventy-two patients with pre-treatment PCa, 17 patients with hormone-refractory metastatic PCa receiving androgen ablation therapy, 20 patients with benign prostatic hypertrophy and 10 healthy male volunteers were enrolled in this retrospective study. The concentration of serum IL-4 was measured by chemiluminescence enzyme immunoassay.


RESULTS
IL-4 induced androgen-response element-driven reporters and activated the AR N-terminal domain (NTD) in a ligand-independent manner in transiently transfected LNCaP cells. Levels of IL-4 in the serum were significantly elevated in patients with hormone-refractory PCa as compared to the levels in pre-treatment PCa.


CONCLUSIONS
IL-4 serum levels were demonstrated to be increased in honnone-refractory PCa and IL-4 was shown to enhance PSA reporter gene activity by the activation of AR NTD in human LNCaP cells. These results suggest that the AR can be activated by cytokines, and that this mechanism may play an important role in the transition from androgen-dependent to androgen-independent PCa after patients receive androgen ablation therapy.
Takeshi
Ueda
U
Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. ueda3713@yahoo.co.jp
Sadar
Marianne D
MD
Suzuki
Hiroyoshi
H
Akakura
Koichiro
K
Sakamoto
Shinichi
S
Shimbo
Masaki
M
Suyama
Takahito
T
Imamoto
Takashi
T
Komiya
Akira
A
Yukio
Naya
N
Ichikawa
Tomohiko
T
D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015847:Interleukin-4 / Q000097:blood* / Q000494:pharmacology; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D011944:Receptors, Androgen; D015847:Interleukin-4; D015741:Metribolone; D017430:Prostate-Specific Antigen