Tumor necrosis factor-alpha inhibits epithelial differentiation and morphogenesis in the mouse metanephric kidney in vitro.

Tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine, has diverse actions both within and outside the immune system and has been implicated in the etiology of a wide range of pathological conditions. Evidence is accumulating that it may also have important roles in the normal development of the embryo. In this study we demonstrated that the addition of recombinant TNF-alpha to metanephric organ culture induced a dose dependent and reversible decrease in growth and development, with inhibition of ureteric bud branching and nephron formation beyond the condensate stage and despite appropriate expression of the transcription factor pax-2. TNF-alpha also increased the point prevalence of apoptosis after only 1 day of culture. We also noted that macrophages were present in renal rudiments at the inception of nephrogenesis and their numbers significantly increased during the culture period. This effect was enhanced by TNF-alpha. We have also demonstrated expression of mRNAs for TNF-alpha and its receptors in whole mouse metanephroi from the inception of renal development. TNF-alpha protein was also detected, predominantly at mesenchymal/epithelial interfaces. In addition, TNF-alpha mRNA and protein were expressed by clonal renal mesenchymal cells in vitro, suggesting that these cells are a source of TNF-alpha in vivo.