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 intercellular adhesion molecule-1 (ICAM-1) are regulated by interferon-gamma 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-gamma-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-gamma 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, beta 2-microglobulin, or ICAM-1, are almost superimposable at each observation time. MHC Class I induction by 6400 units/ml interferon-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 factor-alpha and interferon-gamma is inhibited. Oligo I belongs to a class of active oligodeoxynucleotides that inhibits interferon-gamma-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-gamma-mediated enhancement of both ICAM-1 and MHC Class II DR and the interferon-gamma-mediated reduction in transferrin receptor expression. Thus, oligo I appears to specifically inhibit interferon-gamma-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-gamma with the cell surface, which is a novel mechanism of action for oligodeoxynucleotides.
Ramanathan
M
M
University of California, San Francisco 94143-0640.
Lantz
M
M
MacGregor
R D
RD
Garovoy
M R
MR
Hunt
C A
CA
D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D015395:Histocompatibility Antigens Class I; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma