title: Interleukin-4 in patients with prostate cancer.
abstract: 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.
authors.affiliation: 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
authors.forename: Ueda
authors.initials: U
authors.lastname: Takeshi
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Koichiro
authors.initials: K
authors.lastname: Akakura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimbo
authors.forename: Takahito
authors.initials: T
authors.lastname: Suyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Imamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Komiya
authors.forename: Naya
authors.initials: N
authors.lastname: Yukio
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ichikawa
mesh_terms: 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
chemical_list: D011944:Receptors, Androgen; D015847:Interleukin-4; D015741:Metribolone; D017430:Prostate-Specific Antigen