Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor.
Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Boyu
B
Zhang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Oh-Joon
OJ
Kwon
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Gervaise
G
Henry
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Alicia
A
Malewska
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Xing
X
Wei
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Li
L
Zhang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
William
W
Brinkley
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Yiqun
Y
Zhang
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Patricia D
PD
Castro
Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Mark
M
Titus
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Rui
R
Chen
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Mohammad
M
Sayeeduddin
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ganesh V
GV
Raj
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ryan
R
Mauck
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Claus
C
Roehrborn
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Chad J
CJ
Creighton
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Douglas W
DW
Strand
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX 77030, USA.
Michael M
MM
Ittmann
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: xin@bcm.edu.
Li
L
Xin
D000818:Animals; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007249:Inflammation; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D011467:Prostate / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C410798:AR protein, human; C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C508584:IL1A protein, human; C508585:IL1B protein, human; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D011944:Receptors, Androgen; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
androgen receptor; benign prostatic hyperplasia; epithelial homeostasis; inflammation; interleukin-1; macrophage; microenvironment