SELECTIVE UP-REGULATION OF CYTOKINE-INDUCED RANTES GENE-EXPRESSION INLUNG EPITHELIAL-CELLS BY OVEREXPRESSION OF I-KAPPA-BR

We previously reported the cloning of a cDNA for I kappa BR (for I kap pa B-related) from human lung alveolar epithelial cells, I kappa BR is related to the I kappa B proteins that function as regulators of the NF-kappa B family of transcription factors. Here, we investigated the consequence of I kappa BR overexpression on the expression of NF-kappa B-regulated chemokine genes in lung alveolar epithelial cells. Chemok ines play an important role in many inflammatory diseases such as asth ma and AIDS. Overexpression of I kappa BR in the lung cells resulted i n a rapid 50-100-fold greater production of the RANTES (regulated upon activation, normal T expressed and presumably secreted) protein upon cytokine-induction compared with control cells, I kappa BR overexpress ion, however, did not enhance interleukin-8 or MIP-1 alpha gene expres sion, despite the fact that the expression of all three chemokine gene s are regulated by NF-kappa B, The up-regulation of RANTES gene expres sion resulting from overexpression of I kappa BR correlated with incre ased amounts of a unique RANTES-kappa B binding activity and decreased binding of p50 homodimers, Previous studies have shown that p50 homod imers function as repressors of certain KB sites, Our studies suggest that I kappa BR can aid activation of select NF-kappa B-regulated gene s by sequestering p50 homodimers.