Interleukin-1 alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia

Benign prostatic hyperplasia (BPN) is an extremely common disease of older men In which there is benign overgrowth of the prostatic transition zone, l eading to obstruction of urine outflow, FGF7, a potent growth factor for pr ostatic epithelial cells, is increased by threefold in BPH and is correlate d with increased epithelial proliferation in this condition. Immunohistoche mistry of normal and hyperplastic prostate revealed that FGF7-expressing fi broblastic cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF7 expre ssion by stromal cells. Conditioned medium (CM) from primary cultures of pr ostatic epithelial cells was capable of inducing a two- to sixfold increase in time expression of FGF7 by primary stromal cultures. Blocking experimen ts with neutralizing anti-interleukin-1 alpha(I1-1 alpha) antibodies and IL -1Ra, an I1-1 alpha receptor antagonist, show that this inducing activity w as due to the presence of I1-1 alpha in the epithelial CM. Analysis of norm al prostatic peripheral zone and BPH tissue by enzyme-linked immunoabsorpti on assay reveal that I1-1 alpha is present at increased levels in hyperplas tic prostate and that levels of I1-1 alpha correlate strongly with tissue F GF7 concentration In BPH, Therefore I1-1 alpha is produced by prostatic epi thelial cells and can induce FGF7, a potent epithelial growth factor, which can in turn lead to further epithelial growth and increased I1-1 alpha sec retion, thus establishing a double paracrine loop that is functionally equi valent to an autocrine growth loop. This double paracrine loop may play a k ey role in the abnormal proliferation of the transition zone, which is crit ical to the pathogenesis of BPH.