CHARACTERIZATION OF THE OLIGODEOXYNUCLEOTIDE-MEDIATED INHIBITION OF INTERFERON-GAMMA-INDUCED MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I AND INTERCELLULAR-ADHESION MOLECULE-1

The major histocompatibility complex (MHC) Class I and II genes and in tercellular adhesion molecule-1 (ICAM-1) are regulated by interferon-g amma in a variety of cell types. We have previously shown that the oli godeoxynucleotide 5'-GGG GTT GGT TGT GTT GGG TGT TGT GT-RNH(2) (oligo I) inhibits the interferon-gamma-mediated enhancement of MHC Class I a nd 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-gamma to cells. We also show that the dose-r esponse curves, the selectivity profile, and the kinetics of oligo I a re consistent with this novel mechanism of action. The dose-response c urves for oligo I, obtained using antibodies against the MHC Class I h eavy chain, beta(2)-microglobulin, or ICAM-1, are almost superimposabl e at each observation time. MHC Class I induction by 6400 units/ml int erferon-alpha or interferon-beta or ICAM-1 enhancement by 800 units/ml tumor necrosis factor-alpha is not inhibited by oligo I. However, the synergistic induction of MHC Class I by mixtures of tumor necrosis fa ctor-alpha and interferon-gamma is inhibited. Oligo I belongs to a cla ss of active oligodeoxynucleotides that inhibits interferon-gamma-indu ced MHC Class I and ICAM-1 in K562 cells. The activity and potency is sequence-dependent, but remarkably different sequences can have compar able effects. The activity of oligo I in the HeLa S3 cell line inhibit s the interferon-gamma-mediated enhancement of both ICAM-1 and MHC Cla ss II DR and the interferon-gamma-mediated reduction in transferrin re ceptor expression. Thus, oligo I appears to specifically inhibit inter feron-gamma-induced changes in protein expression, which is consistent with oligo I acting at an early step(s) in the induction process. Tak en together, our results show that oligo I exerts its effects by inhib iting the association of interferon-gamma with the cell surface, which is a novel mechanism of action for oligodeoxynucleotides.