Dihydrotestosterone increases cytotoxic activity of macrophages on prostate cancer cells via TRAIL

Lee, Geun Taek; Kim, Jeong Hyun; Kwon, Seok Joo; Stein, Mark N.; Hong, Jeong Hee; Nagaya, Naoya; Billakanti, Sachin; Kim, Melina Minji; Kim, Wun-Jae; Kim, Isaac Yi

doi:10.1210/en.2019-00367

Cited by 19 publications

(14 citation statements)

References 48 publications

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“…Phagocytosis was increased by testosterone in rat peritoneal macrophages at 10 −12 M but not at concentrations lower or higher than 10 −12 M ( 206 ). Cytotoxicity of RAW macrophages to the mouse prostate cancer cell line, TRAMP C2, was enhanced by DHT alone ( 193 ). This was attributed to enhanced expression of the M1 polarization markers, TRAIL and TNF-α, in the macrophages.…”

Section: Effects Of Androgen Exposure On Monocytes Macrophages mentioning

confidence: 99%

Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

2020

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Androgens, the predominant male sex hormones, drive the development and maintenance of male characteristics by binding to androgen receptor (AR). As androgens are systemically distributed throughout the whole organism, they affect many tissues and cell types in addition to those in male sexual organs. It is now clear that the immune system is a target of androgen action. In the lungs, many immune cells express ARs and are responsive to androgens. In this review, we describe the effects of androgens and ARs on lung myeloid immune cells-monocytes and macrophages-as they relate to health and disease. In particular, we highlight the effect of androgens on lung diseases, such as asthma, chronic obstructive pulmonary disease and lung fibrosis. We also discuss the therapeutic use of androgens and how circulating androgens correlate with lung disease. In addition to human studies, we also discuss how mouse models have helped to uncover the effect of androgens on monocytes and macrophages in lung disease. Although the role of estrogen and other female hormones has been broadly analyzed in the literature, we focus on the new perspectives of androgens as modulators of the immune system that target myeloid cells during lung inflammation.

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Section: Effects Of Androgen Exposure On Monocytes Macrophages mentioning

confidence: 99%

Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

2020

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“…Sex differences are also evident in the immune response to infection, and vary somewhat by model. Males tend to have more circulating M1 macrophages during infection ( 72 ), and dihydrotestosterone (DHT) can induce a prolonged M1 macrophage polarization state in vitro ( 73 ). Females typically exhibit more intense inflammatory responses to multiple microbial stimuli (including vaccines), and have more efficient phagocytic macrophages and increased levels of Toll-like receptors (TLRs) and pro-inflammatory cytokines ( 74 , 75 ).…”

Section: Introductionmentioning

confidence: 99%

Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring

et al. 2020

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Ascending bacterial pyelonephritis, a form of urinary tract infection (UTI) that can result in hospitalization, sepsis, and other complications, occurs in ∼250,000 US patients annually; uropathogenic Escherichia coli (UPEC) cause a large majority of these infections. Although UTIs are primarily a disease of women, acute pyelonephritis in males is associated with increased mortality and morbidity, including renal scarring, and end-stage renal disease. Preclinical models of UTI have only recently allowed investigation of sex and sex-hormone effects on pathogenesis. We previously demonstrated that renal scarring after experimental UPEC pyelonephritis is augmented by androgen exposure; testosterone exposure increases both the severity of pyelonephritis and the degree of renal scarring in both male and female mice. Activin A is an important driver of scarring in non-infectious renal injury, as well as a mediator of macrophage polarization. In this work, we investigated how androgen exposure influences immune cell recruitment to the UPEC-infected kidney and how cell-specific activin A production affects post-pyelonephritic scar formation. Compared with vehicle-treated females, androgenized mice exhibited reduced bacterial clearance from the kidney, despite robust myeloid cell recruitment that continued to increase as infection progressed. Infected kidneys from androgenized mice harbored more alternatively activated (M2) macrophages than vehicle-treated mice, reflecting an earlier shift from a pro-inflammatory (M1) phenotype. Androgen exposure also led to a sharp increase in activin A-producing myeloid cells in the infected kidney, as well as decreased levels of follistatin (which normally antagonizes activin action). As a result, infection in androgenized mice featured prolonged polarization of macrophages toward a pro-fibrotic M2a phenotype, accompanied by an increase in M2a-associated cytokines. These data indicate that androgen enhancement of UTI severity and resulting scar formation is related to augmented local activin A production and corresponding promotion of M2a macrophage polarization.

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“…In cancer, the tumor microenvironment makes the polarization balance of macrophages tend to M2 phenotype [25]. Besides, it has been con rmed that Dihydrotestosterone (DHT) increases the cytotoxic activity of macrophages through the up-regulation of TNF-related apoptosisinducing ligand (TRAIL), while castration induces the proliferation of androgen-resistant CaP cells by reducing the activity of macrophages [26,27]. This is consistent with our results that the proportion of macrophages M0 and M2 in PCa is signi cantly higher than that in normal tissues, androgen can activate macrophages, and the current observations may be of great signi cance for the implementation of immunotherapy in CaP.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of an Immune Microenvironment Based Prognostic Signature and Signal Pathways in Prostate Cancer

et al. 2020

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Background The study of the PCa immune microenvironment has brought new opportunities for the clinical diagnosis and treatment of PCa, but the current study has failed to obtain satisfactory results. We aim to develop a generalized, individualized immune prognostic signature that can improve the survival rate of patients. Methods We collected a total of 591 sample data from the TCGA and GEO cohorts, and evaluated the abundance and distribution of immune cell members in the mixed cell population in the gene expression matrix by CIBERSORT, ESTIMATE, ssGSEA, and other methods. Calculate the TMB value of the mutant gene to evaluate the reliability of PCa for immunotherapy. Besides, the genes related to the immune microenvironment and mutation load of PCa are obtained, and the target genes are obtained by the intersection with the immune-related genes in the ImmPort database. And perform pan-cancer analysis of

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Dihydrotestosterone increases cytotoxic activity of macrophages on prostate cancer cells via TRAIL

Cited by 19 publications

References 48 publications

Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring

Development and Validation of an Immune Microenvironment Based Prognostic Signature and Signal Pathways in Prostate Cancer

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