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Hormones and Cancer

, Volume 2, Issue 3, pp 145–156 | Cite as

Testosterone Regulates Tight Junction Proteins and Influences Prostatic Autoimmune Responses

  • Jing Meng
  • Elahe A. Mostaghel
  • Funda Vakar-Lopez
  • Bruce Montgomery
  • Larry True
  • Peter S. Nelson
Article

Abstract

Testosterone and inflammation have been linked to the development of common age-associated diseases affecting the prostate gland including prostate cancer, prostatitis, and benign prostatic hypertrophy. We hypothesized that testosterone regulates components of prostate tight junctions which serve as a barrier to inflammation, thus providing a connection between age- and treatment-associated testosterone declines and prostatic pathology. We examined the expression and distribution of tight junction proteins in prostate biospecimens from mouse models and a clinical study of chemical castration, using transcript profiling, immunohistochemistry, and electron microscopy. We determined that low serum testosterone is associated with reduced transcript and protein levels of Claudin 4 and Claudin 8, resulting in defective tight junction ultrastructure in benign prostate glands. Expression of Claudin 4 and Claudin 8 was negatively correlated with the mononuclear inflammatory infiltrate caused by testosterone deprivation. Testosterone suppression also induced an autoimmune humoral response directed toward prostatic proteins. Testosterone supplementation in castrate mice resulted in re-expression of tight junction components in prostate epithelium and significantly reduced prostate inflammatory cell numbers. These data demonstrate that tight junction architecture in the prostate is related to changes in serum testosterone levels, and identify an androgen-regulated mechanism that potentially contributes to the development of prostate inflammation and consequent pathology.

Keywords

Testosterone supplementation Inflammation Tight junction Claudin 

Notes

Acknowledgments

We thank Phil Gafken and the FHCRC Proteomics Core facility for assistance with mass spectrometry. This work was supported in part by a grant from the AUA Foundation Research Scholars Program (Solvay Pharmaceuticals) (JM), the Prostate Cancer Foundation (EM, PSN), U54 HD042454 (PSN), U54 CA126540 (PSN), R01 DK069690, and the NIH/NCI Pacific Northwest Prostate SPORE Grant, P50CA97186 (JM, EM, RBM, LT, and PSN).

Supplementary material

12672_2010_63_MOESM1_ESM.doc (146 kb)
Supplemental Figure 1 Claudin expression in normal mouse prostate epithelium. The relative abundance of Cldn1, 3, 4, 7, 8, 10, 11, 12, and 23 in the prostate epithelium of normal mice was normalized to Hprt (Delta CT = CT of Hprt − CT of Claudins). (DOC 146 kb)
12672_2010_63_MOESM2_ESM.doc (242 kb)
Supplemental Figure 2 Testosterone replacement induces Claudin expression in prostate epithelium of castrate mice. a Cldn4 protein expression was restored in the prostates of castrated mice following 2 weeks of testosterone supplementation (lower panel) compared to the castrated mice before testosterone treatment (upper panel). Scale bar = 20 μm, applied to all images. b Cldn8 protein expression was restored in the prostates of castrated mice (lower panel) compared to the castrated mice before testosterone treatment (upper panel). Scale bar = 20 μm, applied to all images. (DOC 242 kb)
12672_2010_63_MOESM3_ESM.doc (136 kb)
Supplemental Figure 3 Expression profile of CLDNs in benign prostate epithelium of men. The relative abundance of CLDN1, 3, 4, 5, 7, 8 ,19, 22, 23 in benign prostate epithelium of men was normalized to RPL13A, (Delta CT=CT of RPL13A–CT of Cldns). (DOC 186 kb)
12672_2010_63_MOESM4_ESM.doc (139 kb)
Supplemental Figure 4 Serum testosterone levels of castrated and testosterone-treated mice. The average serum T level of intact control mice is 13.1 ± 3.4 ng/ml, n = 4. The serum T level became undetectable in the sera of castrated mice. At 14th day post-castration, a group of castrated mice were embedded with T pellets; their serum T levels became 30.0 ± 4.2 ng/ml (n = 2) at day 2 post-T treatment, 28.77 ± 9.4 ng/ml (n = 3) 1 week post-T treatment, and 14.5 ± 0.69 ng/ml (n = 3) 3 weeks post-T supplementation treatment. Another group of castrated mice were embedded with placebo pellets at day 14 post-castration; their serum T levels remained undetectable at 1 week and 3 weeks post-implantation, n = 3. (DOC 173 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jing Meng
    • 1
  • Elahe A. Mostaghel
    • 1
    • 2
  • Funda Vakar-Lopez
    • 3
  • Bruce Montgomery
    • 2
  • Larry True
    • 3
  • Peter S. Nelson
    • 1
    • 2
    • 3
  1. 1.Divisions of Human Biology and Clinical ResearchFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of OncologyUniversity of WashingtonSeattleUSA
  3. 3.Department of PathologyUniversity of WashingtonSeattleUSA

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