The present invention provides both a method and means for regulating I.kappa.B.alpha. degradation, NF.kappa.B activity, and NF.kappa.B-dependent gene expression within living cells, tissues, and organs in-situ. The selective regulation is performed using native PR-39 peptide or one of its shorter-length homologs, for interaction with such I.kappa.B.alpha. and proteasomes as are present in the cytoplasm of viable cells. The result of PR-39 peptide interaction with I.kappa.B.alpha. is a selective alteration in the intracellular proteolytic activity of proteasomes, which in turn, causes a reduction of I.kappa.B.alpha., a decrease of NF.kappa.B activity, and a down-regulation of NF.kappa.B-dependent gene expression.