Abstract
BackgroundRenal tubular epithelial cells (TECs) are one of the main targets of inflammatory insults during interstitial nephritis and kidney transplant rejection. While Th1 cells are know to be essential in the pathogenesis of rejection, the role of Th17 is still under debate. We hypothesize that TECs modulate the outcome of rejection process by production of distinct chemokines and cytokines that determine the attraction of different T-cell subsets. Therefore, we studied differential effects of activated human renal epithelial cells on T-cell migration.MethodsHuman primary TECs were stimulated by IFN-γ and TNF-α in vitro. Chemokines and cytokines produced by activated TECs were measured using Luminex or ELISA. Chemotaxis assay was performed using activated peripheral blood mononuclear cells composed of CD4+CXCR3+ and CD4+CCR6+ T cells migrating towards stimulated and unstimulated TECs.ResultsWhile activated TECs secreted abundant amounts of the pro-inflammatory cytokines IL-6 and IL-8, the T helper cell differentiation cytokines IL-1β, IL-12p70, IL-23 or TGF-β1 were not produced. The production of Th1 chemokines CXCL9, CXCL10 and CCL5 were significantly upregulated after TEC stimulation. In contrast, Th17 chemokine CCL20 could not be detected. Finally, activated TECs attracted significantly higher numbers of CD4+CXCR3+ T cells as compared to unstimulated TECs. No migration of CD4+CCR6+ T cells could be observed.ConclusionActivated primary renal tubular epithelial cells do not attract Th17 cells nor produce cytokines promoting Th17 cell differentiation in our experimental system mimicking the proinflammatory microenvironment of rejection.
Highlights
Tubular Epithelial Cells (TECs) comprise more than 75% of renal parenchymal cells
After 24 hours of stimulation, CD40, HLA-I and HLA-DR cell surface markers were upregulated by tubular epithelial cells (TECs) and remained highly present for at least 72 hours as shown by a significantly higher mean fluorescence intensity (MFI) indicating that TECs are activated in this experimental system (P,0.001) (Figure 1A and Figure 1C)
To define whether TECs are capable of production of cytokines by which naıve CD4+ T cells may differentiate into Th1 and/or Th17 cells or change the cytokine profile of Th1 and Th17 cells, we stimulated TECs (N = 10) with IFN-c/TNF-a and analyzed the cytokine profile of supernatants harvested under these stimulatory conditions compared to the unstimulated state
Summary
Tubular Epithelial Cells (TECs) comprise more than 75% of renal parenchymal cells. Their susceptibility and resistance to both inflammation and apoptosis directs the long-term function of kidney transplants, as tubular injury can be a major cause of nephron loss [1]. Mechanisms of rejection entail a multi-cellular inflammatory process where local environment and multi-directional interplays between T cells and parenchymal cells such as tubular epithelial cells will determine the final outcome [2,3]. Renal tubular epithelial cells (TECs) are one of the main targets of inflammatory insults during interstitial nephritis and kidney transplant rejection. We hypothesize that TECs modulate the outcome of rejection process by production of distinct chemokines and cytokines that determine the attraction of different T-cell subsets. We studied differential effects of activated human renal epithelial cells on T-cell migration
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