Osmotic response element is required for the induction of aldose reductaseby tumor necrosis factor-alpha

Induction of aldose reductase (AR) was observed in human cells treated with tumor necrosis factor-alpha (TNF-alpha). AR protein expression increased s everalfold in human liver cells after 1 day of exposure to 100 units/ml TNF -a. An increase in AR transcripts was also observed in human liver cells af ter 3 h of TNF-alpha treatment, reaching a maximum level of 11-fold at 48 h , Among the three inflammatory cytokines: TNF-alpha, interleukin-1, and int erferon-gamma, TNF-alpha (100 units/ml) gave the most induction of AR. Diff erences in the pattern of AR induction were observed in human liver, lens, and retinal pigment epithelial cells with increasing concentrations of TNF- alpha. A similar pattern of AR promoter response was observed between TNF-a lpha and osmotically stressed human liver cells. The deletion of the osmoti c response element (ORE) abolished the induction by TNF-alpha and osmotic s tress. A point mutation that converts ORE to a nuclear factor-kappa B (NF-k appa B) sequence abolished the osmotic response but maintained the TNF-alph a response. Electrophoretic gel mobility shift assays showed two NF-kappa B proteins, p50 and p52, capable of binding ORE sequence, and gel shift West ern assay detected NF-kappa B proteins p50 and p65 in the ORE complex. Inhi bitors of NF-kappa B signaling, lactacystin, and MG132 abolished the AR pro moter response to TNF-alpha.