Production of inflammatory mediators by renal epithelial cells is insensitive to glucocorticoids.
1. In the present study we investigated the effect of glucocorticoids on the activation of renal tubular epithelial cells, which are thought to play an important role in inflammatory processes in the kidney. 2. Activation of renal epithelial cells by IL-1, TNF-alpha or CD40L resulted in increased production of cytokines and chemokines. Both in the renal epithelial cell line HK-2 and in primary cultures of human proximal tubular epithelial cells (PTEC) production of IL-6, IL-8 and monocyte chemotactic protein 1 (MCP-1) was not inhibited by glucocorticoids, independent of the stimulus. 3. In contrast, dexamethasone strongly inhibited cytokine production by immortalized renal fibroblasts and an airway epithelial cell line (A549). 4. Stimulation of renal epithelial cells resulted in activation of NF-kappaB, a pivotal transcription factor in the regulation of cytokine genes, as was shown by IkappaB-alpha degradation and increased DNA-binding activity. In contrast to dexamethasone, addition of the NF-kappaB inhibitors pyrrolidine dithiocarbamate (PDTC) and n-tosyl-l-phenylalanine chloromethyl ketone (TPCK) completely abolished cytokine and chemokine production. 5. Renal epithelial cells express abundant levels of the functional glucocorticoid receptor alpha (GRalpha) isoform and low levels of the inhibitory beta isoform (GRbeta). 6. In conclusion, cytokine production by renal epithelial cells is insensitive to the inhibitory effects of glucocorticoids. The lack of dexamethasone-mediated inhibition was specific for renal epithelial cells and could not be explained by an increased expression of the glucocorticoid receptor beta isoform.
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Simone
S
de Haij
Andrea M
AM
Woltman
Astrid C
AC
Bakker
Mohamed R
MR
Daha
Cees
C
van Kooten
D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D003907:Dexamethasone