title: Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells.
abstract: Progression of benign prostatic hyperplasia (BPH) involves chronic inflammation and immune dysregulation. Preclinical studies have demonstrated that prostate inflammation and tissue remodeling are exacerbated by hypogonadism and prevented by testosterone supplementation. We now investigated whether, in humans, hypogonadism was associated with more severe BPH inflammation and the in vitro effect of the selective androgen receptor agonist dihydrotestosterone (DHT) on cultures of stromal cells derived from BPH patients (hBPH). Histological analysis of inflammatory infiltrates in prostatectomy specimens from a cohort of BPH patients and correlation with serum testosterone level was performed. Even after adjusting for confounding factors, hypogonadism was associated with a fivefold increased risk of intraprostatic inflammation, which was also more severe than that observed in eugonadal BPH patients. Triggering hBPH cells by inflammatory stimuli (tumor necrosis factor α, lipopolysaccharide, or CD4(+)T cells) induced abundant secretion of inflammatory/growth factors (interleukin 6 (IL6), IL8, and basic fibroblast growth factor (bFGF)). Co-culture of CD4(+)T cells with hBPH cells induced secretion of Th1 inducer (IL12), Th1-recruiting chemokine (interferon γ inducible protein 10, IP10), and Th2 (IL9)- and Th17 (IL17)-specific cytokines. Pretreatment with DHT inhibited NF-κB activation and suppressed secretion of several inflammatory/growth factors, with the most pronounced effects on IL8, IL6, and bFGF. Reduced inflammatory cytokine production by T-cells, an increase in IL10, and a significant reduction of T cells proliferation suggested that DHT exerted a broad anti inflammatory effect on testosterone cells [corrected]. In conclusion, our data demonstrate that DHT exerts an immune regulatory role on human prostatic stromal cells, inhibiting their potential to actively induce and/or sustain autoimmune and inflammatory responses.
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, Florence 50139, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cellai
authors.forename: Raffaella
authors.initials: R
authors.lastname: Santi
authors.forename: Letizia
authors.initials: L
authors.lastname: Lombardelli
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.forename: Federica
authors.initials: F
authors.lastname: Logiodice
authors.forename: Marco
authors.initials: M
authors.lastname: Carini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nesi
authors.forename: Mauro
authors.initials: M
authors.lastname: Gacci
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Piccinni
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D011470:Prostatic Hyperplasia / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000728:Androgens; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D011944:Receptors, Androgen; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D013196:Dihydrotestosterone; D013739:Testosterone; D051546:Cyclooxygenase 2