title: TNF is necessary for castration-induced prostate regression, whereas TRAIL and FasL are dispensable.
abstract: TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal. Employing high-resolution serial magnetic resonance imaging to measure mouse prostate volume changes over time, we demonstrate that the extent of castration-induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes but not mice deficient for TNF-related apoptosis-inducing ligand or Fas signaling. Wild-type mice receiving soluble TNF (sTNF) receptor 2 (to bind TNF and block signaling) before castration exhibit an identical reduction of prostate regression. Together, these data indicate that uniquely among known extrinsic death signals, TNF is required for castration-induced prostate regression. Additionally, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate after castration. This is consistent with a paracrine role for TNF in prostate regression. When injected into the peritoneum of Tnf(-/-) mice at the time of castration, sTNF restores normal levels of prostate regression. However, wild-type mice receiving sTNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient but acts in the context of additional castration-induced signals. These findings support a physiologic role for TNF in prostate regression after androgen withdrawal. Understanding this role may lead to novel therapies for prostate cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, California 92697-4800, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Davis
authors.forename: Kent L
authors.initials: KL
authors.lastname: Nastiuk
authors.forename: John J
authors.initials: JJ
authors.lastname: Krolewski
mesh_terms: D000728:Androgens / Q000172:deficiency; D000818:Animals; D017209:Apoptosis; D002369:Castration; D004847:Epithelial Cells; D053222:Fas Ligand Protein / Q000172:deficiency / Q000378:metabolism; D015151:Immunoblotting; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000728:Androgens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha