Decorin and biglycan are closely related abundant extracellular matrix proteoglycans that have been shown to bind to C1q. Given the overall structural similarities between C1q and mannose-binding lectin (MBL), the two key recognition molecules of the classical and the lectin complement pathways, respectively, we have examined functional consequences of the interaction of C1q and MBL with decorin and biglycan. Recombinant forms of human decorin and biglycan bound C1q via both collagen and globular domains and inhibited the classical pathway. Decorin also bound C1 without activating complement. Furthermore, decorin and biglycan bound efficiently to MBL, but only biglycan could inhibit activation of the lectin pathway. Other members of the collectin family, including human surfactant protein D, bovine collectin-43, and conglutinin also showed binding to decorin and biglycan. Decorin and biglycan strongly inhibited C1q binding to human endothelial cells and U937 cells, and biglycan suppressed C1q-induced MCP-1 and IL-8 production by human endothelial cells. In conclusion, decorin and biglycan act as inhibitors of activation of the complement cascade, cellular interactions, and proinflammatory cytokine production mediated by C1q. These two proteoglycans are likely to down-regulate proinflammatory effects mediated by C1q, and possibly also the collectins, at the tissue level.

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1 In the present study we investigated the eect of glucocorticoids on the activation of renal tubular epithelial cells, which are thought to play an important role in in¯ammatory processes in the kidney. 2 Activation of renal epithelial cells by IL-1, TNF-a 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 ®broblasts and an airway epithelial cell line (A549). 4 Stimulation of renal epithelial cells resulted in activation of NF-kB, a pivotal transcription factor in the regulation of cytokine genes, as was shown by IkB-a degradation and increased DNA-binding activity. In contrast to dexamethasone, addition of the NF-kB 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 (GRa) isoform and low levels of the inhibitory beta isoform (GRb). 6 In conclusion, cytokine production by renal epithelial cells is insensitive to the inhibitory eects of glucocorticoids. The lack of dexamethasone-mediated inhibition was speci®c for renal epithelial cells and could not be explained by an increased expression of the glucocorticoid receptor beta isoform.

Interaction of tubular epithelial cells and kidney infiltrating T cells via ICOS-L and B7-H1 may change the balance of positive and negative signals to the T cells, leading to IL-10 production and limitation of local immune responses.

From these results, we conclude that donor-derived endothelial cell chimerism results from repair of damaged endothelium and maintenance of vascular homeostasis. In contrast, epithelial cell chimerism follows a more uniform pattern of engraftment, not influenced by tissue damage.

Glucocorticoids modulate cellular and inflammatory responses via stimulation or inhibition of gene transcription. Inhibition of cytokine gene expression is mediated via repression of transcription factors, including NF-B. Previously we have shown that cytokine production by renal epithelial cells is insensitive to the inhibitory action of dexamethasone. In this study we demonstrate that dexamethasone is unable to inhibit NF-B activation in the renal epithelial cell line HK-2, as measured by I B-␣ degradation and DNA binding activity. Transfection of an NF-B-inducible reporter gene demonstrated that non-stimulated HK-2 cells contain a high level of constitutively active NF-B compared with the steroid-sensitive airway epithelial cell line A549, which was not blocked by dexamethasone. Expression and nuclear translocation of the glucocorticoid receptor (GR) was comparable in both cell types. In HK-2 cells, dexamethasone stimulated expression of two glucocorticoidresponsive genes, ␤ 2 -adrenoreceptors and angiotensinogen. The capacity of GR to transactivate the native angiotensinogen glucocorticoid-responsive element (GRE) using chromatin-IP was not impaired. Moreover, dexamethasone activation of a GRE-driven reporter construct appeared to be equally effective, although less sensitive compared with A549 cells. In conclusion, we provide evidence that glucocorticoids are unable to repress the activity of NF-B in renal epithelial cells in the presence of an intact stimulatory pathway.