We have previously documented that human mesangial cell (HMC)-derived TNF-alpha is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the role of mesangial cells in the activation of podocytes in IgAN. There was no binding of IgA from patients with IgAN to podocytes. Podocytes cultured with IgA from patients with IgAN did not induce the release of growth factors or cytokines. Furthermore, podocytes did not express mRNA of known IgA receptors. In contrast, IgA-conditioned medium (IgA-HMC medium) prepared by culturing HMC with IgA from patients with IgAN for 48 h significantly increased the gene expression and protein synthesis of TNF-alpha by podocytes with a 17-fold concentration above that of IgA-HMC medium. The upregulation of TNF-alpha expression by podocyte was only abolished by a neutralizing antibody against TNF-alpha but not by other antibodies. Exogenous TNF-alpha upregulated the synthesis of TNF-alpha by podocytes in an autocrine fashion. IgA-HMC medium prepared with IgA from patients with IgAN also significantly upregulated the expression of both TNF-alpha receptor 1 and 2 in podocytes. Our in vitro finding suggests podocytes may play a contributory role in the development of interstitial damage in IgAN by amplifying the activation of tubular epithelial cells with enhanced TNF-alpha synthesis after inflammatory changes of HMC.