Impact of steroid hormone environment on immune cell phenotype and function

Gender differences are increasingly recognised as factors in disease susceptibility, drug response and immune cell function. However, the underpinning biology is less well understood. Sex steroids including androgens are master regulators of cell function with well-established roles in regulation of metabolism, reproduction and cancers.

Androgens act through the androgen receptor and function as 'Goldilocks factors' with either too little, or too much, having an adverse effect on tissue function. Androgen concentrations differ with age, sex and disease which may underpin differences in prevalence and prognosis of several inflammatory disorders such as cardiovascular disease and rheumatoid arthritis. Androgen replacement has benefits for men with low testosterone (due to hypogonadism) and may have more general health benefits for ageing men and women by maintaining muscle and bone integrity and cardiovascular health - although this is controversial. The impact of androgens and androgen therapies on the immune landscape and aging immune system has largely been unexplored. This is important as changes in the immune system can increase susceptibility to infection or cancer progression if underactive and enhance susceptibility to autoimmunity and inflammatory diseases if overactivated.

We aim to investigate the regulation of androgen receptor expression and function in response to hormonal and immune cell modulators in macrophages and other immune cells as key regulators in health and disease.

Specific Research Questions and Objectives
1. Is the androgen receptor gene and/or protein differentially regulated in immune cells?
2. Do androgens alter the phenotype and/or function of immune cells?

As the androgen receptor acts as the gatekeeper for androgen action it is essential, we gain a full understanding of the molecular systems responsible for controlling expression and activation in diverse tissues. Using molecular biology approaches we have recently identified and characterised a novel binding site for androgen receptor, within its own gene, which mediates regulation of receptor expression in a cell type-dependent manner. We have established cell resources from male (prostate) and female (endometrium, breast) tissues and developed primary and co-culture systems to investigate immune cell cross-talk. Furthermore, we have established key functional assays for assessing the impacts of receptor agonists. We are therefore uniquely positioned to investigate and compare the molecular basis for regulation of the androgen receptor mRNA and protein and how this impact on immune cell phenotype and function.