The prognostic value of peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma.

OBJECTIVE: To investigate the prognostic value of regulatory T cells (Tregs) and its correlation with cyclooxygenase-2 (COX-2) expression in clear cell renal cell carcinoma (RCC). PATIENTS AND METHODS: CD4+, Foxp3+ tumour-infiltrating lymphocytes and tumour COX-2 expression were assessed by immunohistochemistry in tissue microarrays containing RCC from 125 patients. Prognostic effects of low and high expression were evaluated by Cox regression and Kaplan-Meier analysis using the median values as thresholds. The expression of Tregs and COX-2 were compared with the clinicopathological variables. In addition, Tregs and its correlation with COX-2 expression was also analysed. RESULTS: Peritumoral Tregs were positively correlated with intratumoral COX-2 expression (Spearman rank correlation 0.336, P < 0.001). Peritumoral Tregs were associated with TNM stage (P = 0.001) and tumour size (P = 0.002), while intratumoral COX-2 expression was associated with TNM stage (P = 0.018) and grade (P = 0.013). Using multivariate analysis, increased peritumoral Tregs, higher TNM stage (III + IV), larger tumour size (> or =7 cm) and higher nuclear grade (III + IV) were independent predictors for significantly shorter overall survival and disease-free survival. CONCLUSIONS: Increased peritumoral Tregs are associated with worse prognosis in clear cell RCC. The high intratumoral COX-2 expression may be the underlying reason for the aberrant gathering of Tregs. These results suggest that clinical application of COX-2 inhibitors may benefit those patients with higher intratumoral COX-2 immunostaining by reducing the transformation of Tregs in RCC.

Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-kappaB activation.

Hyperhomocysteinemia, or an elevation of blood homocysteine (Hcy) levels, is associated with cardiovascular disorders. Although kidney dysfunction is an important risk factor causing hyperhomocysteinemia, the direct effect of Hcy on the kidney is not well documented. There is a positive association between an elevation of blood Hcy levels and the development of chronic kidney disease. Inflammatory response such as increased chemokine expression has been implicated as one of the mechanisms for renal disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in renal disease. Nuclear factor-kappaB (NF-kappaB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underlining such an effect in rat kidneys as well as in proximal tubular cells. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 12 wk. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-kappaB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-kappaB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-kappaB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-kappaB oligodeoxynucleotide to inhibit NF-kappaB activation. Such a treatment prevented Hcy-induced MCP-1 mRNA expression in tubular cells. Our results suggest that hyperhomocysteinemia stimulates MCP-1 expression in the kidney via NF-kappaB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia.

Enhanced MCP-1 expression during ischemia/reperfusion injury is mediated by oxidative stress and NF-kappaB.

BACKGROUND: Renal ischemia/reperfusion injury is a major cause of acute renal failure in both native kidneys and renal allografts. One important feature of such injury is monocyte/macrophage infiltration into the renal tissue. The infiltration of monocytes/macrophages can be induced by chemotactic factors produced by renal cells. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant protein for monocyte recruitment. The objective of the present study was to investigate mechanisms of elevated MCP-1 expression in rat kidney during ischemia/reperfusion injury. METHODS: The left kidney was subjected to one hour of ischemia followed by reperfusion for various time periods. The expression of MCP-1 mRNA was determined by nuclease protection assay and MCP-1 protein was identified by immunohistochemistry. Activation of a nuclear factor-kappa B (NF-kappaB) was determined by electrophoretic mobility shift assay and the level of lipid peroxides in the kidney was measured. RESULTS: There was a significant increase in MCP-1 expression in the ischemia/reperfusion kidney 2 hours after reperfusion (210% of the control). This increase was accompanied by activation of NF-kappaB, suggesting that this transcription factor might be involved in the event. The number of monocytes was significantly elevated in the kidney 3 days after ischemia/reperfusion. Pretreatment of rats with NF-kappaB inhibitors not only prevented NF-kappaB activation induced by ischemia/reperfusion, but also inhibited MCP-1 mRNA expression. Further analysis revealed that oxidative stress and increased IkappaB-alpha phosphorylation might be an underlying mechanism for NF-kappaB activation and subsequent MCP-1 mRNA expression in the ischemia/reperfusion kidney. CONCLUSION: The present study clearly demonstrates that enhanced MCP-1 expression in rat kidney during ischemia/reperfusion injury is mediated by NF-kappaB activation and oxidative stress. Elevated MCP-1 expression might be responsible for increased monocyte infiltration in the injured kidney.