Abstract
Renal tubular epithelial cells are a central cell type in tubulointerstitial inflammation because they can produce inflammatory mediators such as cytokines and chemokines. Several signals derived from either monocytes or activated T cells have been reported to regulate the activation of tubular epithelial cells. We studied this regulation in more detail by combined treatment with CD40 ligand and the proinflammatory cytokine interleukin-1 (IL-1) in vitro. The regulation of cytokine and chemokine production was studied in primary cultures of human proximal tubular epithelial cells (PTECs). PTECs were activated by coculture with CD40L-transfected murine fibroblasts in combination with recombinant human cytokines. The production of IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and RANTES were measured by specific enzyme-linked immunosorbent assay. The combined activation of PTECs with CD40L and IL-1 resulted in strong synergistic effects on the production of IL-6, IL-8, and RANTES, whereas only an additive stimulation of MCP-1 production was observed. The effects were specific for IL-1 and could be neutralized by the addition of the IL-1R antagonist. Both IL-1alpha and IL-1beta showed similar effects on cytokine production by PTECs. The effects of IL-1 were dose dependent, and kinetic experiments showed that synergistic effects were observed after 24 hours of activation and remained present for at least five days. Reverse transcription-polymerase chain reaction analysis showed that human PTECs could express both IL-1alpha and IL-1beta. The activation of PTECs with IL-1 resulted in an up-regulation of CD40 expression on these cells. A complex network of regulation exists for the production of cytokines and chemokines by PTECs. The combined treatment results in strong synergistic effects on IL-6, IL-8, and RANTES production. This strengthens the potential role of tubular epithelial cells in inflammatory responses within the kidney.
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