Interleukin-1α Is a Paracrine Inducer of FGF7, a Key Epithelial Growth Factor in Benign Prostatic Hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men in which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow. FGF7, a potent growth factor for prostatic epithelial cells, is increased by threefold in BPH and is correlated with increased epithelial proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF7-expressing fibroblastic cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF7 expression by stromal cells. Conditioned medium (CM) from primary cultures of prostatic epithelial cells was capable of inducing a two- to sixfold increase in the expression of FGF7 by primary stromal cultures. Blocking experiments with neutralizing anti-interleukin-1alpha (Il-1alpha) antibodies and IL-1Ra, an Il-1alpha receptor antagonist, show that this inducing activity was due to the presence of Il-1alpha in the epithelial CM. Analysis of normal prostatic peripheral zone and BPH tissue by enzyme-linked immunoabsorption assay reveal that Il-1alpha is present at increased levels in hyperplastic prostate and that levels of Il-1alpha correlate strongly with tissue FGF7 concentration in BPH. Therefore Il-1alpha is produced by prostatic epithelial cells and can induce FGF7, a potent epithelial growth factor, which can in turn lead to further epithelial growth and increased Il-1alpha secretion, thus establishing a double paracrine loop that is functionally equivalent to an autocrine growth loop. This double paracrine loop may play a key role in the abnormal proliferation of the transition zone, which is critical to the pathogenesis of BPH.