Upregulation of androgen-responsive genes and transforming growth factor-β1 cascade genes in a rat model of non-bacterial prostatic inflammation.
BACKGROUND
Prostatic inflammation is associated with the development of prostatic hyperplasia. We investigated the effects of prostatic inflammation on expression levels of androgen-responsive genes and growth factors in the prostate.


METHODS
Prostatic inflammation was induced by formalin injection into bilateral ventral lobes of the prostate of male SD rats. After 28 days, the prostate was harvested for analyses of proinflammatory cytokines, androgen-responsive genes in the epithelium, and TGF-β1 cascade genes in the stroma. Some rats were given a COX-2 inhibitor (celecoxib; 10 mg/kg/day) by oral gavage for 28 days.


RESULTS
The formalin-injected prostate exhibited widespread low-grade inflammation (<50 leukocytes/10,000 μm(2) ) along with focal high-grade inflammation (>100 leukocytes/10,000 μm(2) ) in limited areas. Compared to control, formalin-injected prostate exhibited a 2.5-fold to sixfold increased protein expression of IL-1α, IL-1β, and IL-6. In the low-grade inflammatory regions, threefold to ninefold and twofold to threefold upregulations of mRNA levels of androgen receptors/androgen-responsive genes and TGF-β1 cascade genes were respectively, observed in the epithelium and stroma obtained by laser-capture microdissection. Positive staining for androgen receptors in the epithelial nuclei, and TGF-β1, IL-6, and COX-2 in the stroma was increased in the low-grade inflammation area. COX-2 inhibitor treatment suppressed these upregulations of cytokines, androgen-responsive, and TGF-β1 cascade genes.


CONCLUSIONS
Prostatic inflammation induced increased expression of androgen-responsive genes in the epithelium and TGF-β1 cascade genes in the stroma, which were suppressed by COX-2 inhibitors, suggesting that activation of these genes in the low-grade inflammatory region might be involved in the development of symptomatic BPH.
Departments of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yasuhito
Y
Funahashi
Katherine J
KJ
O'Malley
Naoki
N
Kawamorita
Pradeep
P
Tyagi
Donald B
DB
DeFranco
Ryosuke
R
Takahashi
Momokazu
M
Gotoh
Zhou
Z
Wang
Naoki
N
Yoshimura
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism; D011472:Prostatitis / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000728:Androgens; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D011720:Pyrazoles; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D051546:Cyclooxygenase 2; D000068579:Celecoxib
TGF-β1; androgen receptor; inflammation; laser capture microdissection; prostate