1,25-dihydroxyvitamin D3 differentially regulates IL-1alpha-stimulated IL-8 and MCP-1 mRNA expression and chemokine secretion by human primary proximal tubular epithelial cells.

Beside its role in calcium homeostasis, 1,25-D3 modulates multiple immunological functions in cells of the immune system. In tubular epithelial cells, it increases the expression of HLA-DR and ICAM-1 molecules. Since production of chemokines, such as IL-8 and MCP-1, by tubular epithelial cells is crucial for the inflammatory response in acute transplant rejection and interstitial nephritis, we tested whether 1,25-D3 influences the production of IL-8 and MCP-1 by primary human tubular epithelial cells (TEC). For chemokine detection we used enzyme-linked immunosorbent assays. We differentiated between chemokine secretion directed to the apical and basolateral environment by using cell culture inserts as a model for the tubular basement membrane. mRNA of IL-8 and MCP-1 after stimulation of TEC with IL-1alpha and/or 1,25-D3 was isolated and compared by competitive RT-PCR. We found that basolateral production of IL-8 was higher than luminal secretion. 1,25-D3 (10(-8) M) alone and in combination with IL-1alpha suppressed IL-8 production after 48 h. Basolateral compared to luminal MCP-1 secretion was higher after stimulation either with IL-1alpha alone or combined with 1,25-D3. After 72 h, 1,25-D3 enhanced the IL-1alpha-stimulated MCP-1 secretion. Increased IL-8 mRNA expression after stimulation with IL-1alpha was suppressed by coincubation with 1,25-D3, while MCP-1 mRNA synthesis was enhanced by 1,25-D3 alone and in combination with IL-1 alpha. We conclude that 1,25-D3 differently modulates the expression of CXC-chemokine IL-8 and CC-chemokine MCP-1 by human TEC. The differential effects of 1,25-D3 on renal tubular cytokine secretion have to be considered in therapeutic dials on this hormone, e.g. in renal transplant rejection.