Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo.
Tang, Sydney 1; Leung, Joseph C.K. 1; Abe, Katsushige 3; Chan, Kwok Wah 2; Chan, Loretta Y.Y. 1; Chan, Tak Mao 1; Lai, Kar Neng 1
[Article]
Journal of Clinical Investigation.
111(4):515-527, February 2003.
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Renal tubulointerstitial injury is characterized by inflammatory cell infiltrate; however, the stimuli for leukocyte recruitment are not fully understood. IL-8 is a potent chemokine produced by proximal tubular epithelial cells (PTECs). Whether nephrotic proteins stimulate tubular IL-8 expression remains unknown. Acute exposure of human PTECs to albumin induced IL-8 gene and protein expression time- and dose-dependently. Apical albumin predominantly stimulated basolateral IL-8 secretion. Electrophoretic mobility shift assay demonstrated nuclear translocation of NF-[kappa]B, and the p65/p50 subunits were activated. NF-[kappa]B activation and IL-8 secretion were attenuated by the NF-[kappa]B inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H2O2 stimulated NF-[kappa]B translocation and IL-8 secretion. Albumin-induced ROS generation, NF-[kappa]B activation, and IL-8 secretion were endocytosis- and PKC-dependent as these downstream events were abrogated by the PI3K inhibitors LY294002 and wortmannin, and the PKC inhibitors GF109203X and staurosporin, respectively. In vivo, IL-8 mRNA expression was localized by in situ hybridization to the proximal tubules in nephrotic kidney tissues. The intensity of IL-8 immunostaining was higher in nephrotic than non-nephrotic subjects. In conclusion, albumin is a strong stimulus for tubular IL-8 expression, which occurs via NF-[kappa]B-dependent pathways through PKC activation and ROS generation.
Copyright (C) 2003 The American Society for Clinical Investigation, Inc.