Characterization of the oligodeoxynucleotide-mediated inhibition of interferon-γ-induced major histocompatibility complex class I and intercellular adhesion molecule-1

The major histocompatibility complex (MHC) Class I and II genes and intercellular adhesion molecule-1 (ICAM-1) are regulated by interferon-γ in a variety of cell types. We have previously shown that the oligodeoxynucleotide 5'-GGG GTT GGT TGT GTT GGG TGT TGT GT-RNH₂ (oligo I) inhibits the interferon-γ-mediated enhancement of MHC Class I and ICAM-1 proteins in the K562 cell line. We have now investigated the mechanism of action of oligo I and report that it acts by inhibiting the binding of interferon-γ to cells. We also show that the dose-response curves, the selectivity profile, and the kinetics of oligo I are consistent with this novel mechanism of action. The dose-response curves for oligo I, obtained using antibodies against the MHC Class I heavy chain, β₂-microglobulin, or ICAM-1, are almost superimposable at each observation time. MHC Class I induction by 6400 units/ml interferon-α or interferon-β or ICAM-1 enhancement by 800 units/ml tumor necrosis factor-α is not inhibited by oligo I. However, the synergistic induction of MHC Class I by mixtures of tumor necrosis factor-α and interferon-γ is inhibited. Oligo I belongs to a class of active oligodeoxynucleotides that inhibits interferon-γ-induced MHC Class I and ICAM-1 in K562 cells. The activity and potency is sequence- dependent, but remarkably different sequences can have comparable effects. The activity of oligo I in the HeLa S3 cell line inhibits the interferon-γ- mediated enhancement of both ICAM-1 and MHC Class II DR and the interferon- γ-mediated reduction in transferrin receptor expression. Thus, oligo I appears to specifically inhibit interferon-γ-induced changes in protein expression, which is consistent with oligo I acting at an early step(s) in the induction process. Taken together, our results show that oligo I exerts its effects by inhibiting the association of interferon-γ with the cell surface, which is a novel mechanism of action for oligodeoxynucleotides.