Testicular macrophage modulation of Leydig cell steroidogenesis

This review will highlight recent advances in the study of the immuno-endocrinology of the testis, in particular how macrophage-derived inflammatory mediators affect Leydig cell functions. Both the beneficial and deleterious outcomes resulting from macrophage-Leydig cell interactions are discussed. A brief overview of testicular physiology is provided that discusses the functional and anatomical compartmentalization of the testis into the gamete and endocrine compartments where spermatogenesis and testosterone biosynthesis take place, respectively. The process of steroidogenesis including the activities of the steroidogenic enzymes and the role of steroidogenic acute regulatory protein (StAR) are described. The close physical association between Leydig cells and interstitial testicular macrophages suggests that these cells are functionally related. Under normal physiological and non-inflammatory conditions macrophages play an important role in Leydig cell development. If macrophages are absent from the testicular interstitium, Leydig cells fail to develop normally, which suggest that macrophages provide essential growth and differentiation factors for Leydig cells. In contrast, when macrophages are activated and elaborate inflammatory mediators, Leydig cell steroidogenesis is inhibited. Activated macrophages produce pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) that are profoundly inhibitory to Leydig cells and appear to act as transcriptional repressors of steroidogenic enzyme gene expression. Macrophages also produce reactive oxygen species (ROS) such as hydrogen peroxide, which also inhibits Leydig cell functions. ROS appear to act acutely by perturbing Leydig cell mitochondria resulting in the inhibition of StAR protein expression. One important consequence of this immune modulation of Leydig cell function may be manifest behaviorally by switching the affected animal from 'testosterone' behavior, to 'sickness' behavior. Increased interest in immune-endocrine control of reproductive function over the past decade has stimulated research into the molecular and biochemical immunopathophysiology of the reproductive system. As investigations unravel mechanisms underlying reproductive dysfunction caused by inflammation and infection, an understanding of the role that immune-endocrine interactions play in the normal physiology of the reproductive system has emerged.