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      1,25-Dihydroxyvitamin D 3 Differentially Regulates IL-1α-Stimulated IL-8 and MCP-1 mRNA Expression and Chemokine Secretion by Human Primary Proximal Tubular Epithelial Cells


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          Beside its role in calcium homeostasis, 1,25-D<sub>3</sub> 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-D<sub>3</sub> 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-1α and/or 1,25-D<sub>3</sub> was isolated and compared by competitive RT-PCR. We found that basolateral production of IL-8 was higher than luminal secretion. 1,25-D<sub>3</sub> (10<sup>–8</sup> M) alone and in combination with IL-1α suppressed IL-8 production after 48 h. Basolateral compared to luminal MCP-1 secretion was higher after stimulation either with IL-1α alone or combined with 1,25-D<sub>3</sub>. After 72 h, 1,25-D<sub>3</sub> enhanced the IL-1α-stimulated MCP-1 secretion. Increased IL-8 mRNA expression after stimulation with IL-1α was suppressed by coincubation with 1,25-D<sub>3</sub>, while MCP-1 mRNA synthesis was enhanced by 1,25-D<sub>3</sub> alone and in combination with IL-1 α . We conclude that 1,25-D<sub>3</sub> differently modulates the expression of CXC-chemokine IL-8 and CC-chemokine MCP-1 by human TEC. The differential effects of 1,25-D<sub>3</sub> on renal tubular cytokine secretion have to be considered in therapeutic dials on this hormone, e.g. in renal transplant rejection.

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          1,25–Dihydroxyvitamin D 3 Stimulates Transforming Growth Factor–β1 Synthesis by Mouse Renal Proximal Tubular Cells

          1,25–Dihydroxyvitamin D 3 [1,25–(OH) 2 D 3 ] is a secosteroid hormone with effects on cell growth, differentiation and immunoregulatory functions in a number of tissues not primarily involved in mineral metabolism. We recently demonstrated growth–regulating effects of 1,25–(OH) 2 D 3 on human mesangial cells and proximal tubular cells. To investigate whether 1,25–(OH) 2 D 3 might also affect the synthesis of cytokines and growth factors in proximal tubular cells, we assessed in the present study the expression and secretion of transforming growth factor–β1 (TGF–β1) in a mouse proximal tubular cell line (MCT) in vitro. TGF–β1 synthesis was measured by a monospecific ELISA in culture supernatant. The secreted TGF–β1 was proven to be biologically active by means of a bioassay system (CCL–64 mink lung epithelial cell proliferation assay). TGF–β1 gene expression was assessed by RT–PCR. To analyze whether TGF–β1 expression mediates the 1,25–(OH) 2 D 3 –induced antiproliferative actions in MCT, proliferation studies in the absence or presence of a blocking monoclonal anti TGF–β1–3 antibody were performed. 1,25–(OH) 2 D 3 (10 –11 to 10 –7 M) specifically increased the TGF–β1 protein secretion in MCT with a maximum at 10 –8 M. No detectable effect was found with 25 D 3 at 10 times higher concentrations. A synthetic 20–epi analogue, MC 1288, increased TGF–β1 secretion up to similar amounts at equimolar concentrations as the natural hormone 1,25–(OH) 2 D 3 . Steady–state TGF–β1 mRNA concentration in MCT was transiently increased by 1,25–(OH) 2 D 3 between 12 and 24 h, returning to control values at 48 h. Blocking TGF–β1 did not reduce or abrogate the antiproliferative effect of 1,25–(OH) 2 D 3 . In conclusion, 1,25–(OH) 2 D 3 stimulates TGF–β1 expression in renal proximal tubular cells, a growth factor with anti–inflammatory and profibrotic actions which plays an important role in the development and progression of nephrosclerosis.
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            Local production of inflammatory mediators in an experimental model of acute obstructive pyelonephritis.

            To investigate bacterial growth and inflammatory mediator release in the early stage of the immune response, a unilateral acute ascending pyelonephritis was induced in rats by intrabladder inoculation of Escherichia coli. The infected left kidney showed a significant bacterial proliferation, local production of interleukin (IL)-6 and IL-8 as detected by immunocytochemistry, and extensive destruction of renal parenchyma associated with impressive leukocyte recruitment. Inducible and constitutive nitric oxide synthases (NOS) were locally expressed, and a time-dependent increase in urinary secretion of nitric oxide (NO) was seen that could be blocked by NG-monomethyl-L-arginine. However, there was a discrepancy between the NO profile in the kidney and urine. The results demonstrate that in the early stage of acute pyelonephritis kidney tubules participate actively in the local host response by producing important inflammatory mediators and that urinary NO levels are not suitable for predicting renal NOS activity.
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              Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 2001
                23 April 2001
                : 9
                : 3
                : 223-228
                Department of Medicine I, Medical University of <city>Lübeck</city>, Germany
                52615 Exp Nephrol 2001;9:223–228
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 23, Pages: 6
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/52615
                Self URI (text/html): https://www.karger.com/Article/FullText/52615
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                1,25-Dihydroxycholecalciferol,IL-8,MCP-1,Proximal tubular epithelial cells,Side-dependent secretion,Interstitial nephritis


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