Testosterone Regulates Tight Junction Proteins and Influences Prostatic Autoimmune Responses
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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.
KeywordsTestosterone supplementation Inflammation Tight junction Claudin
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).
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