STIMULATION OF MHC CLASS-I TRANSCRIPTION BY INTERFERON-GAMMA INVOLVESA NON-A, NON-C KINASE IN ADDITION TO PROTEIN-KINASE-C

The signal pathways by which interferon-gamma (IFN-gamma) is able to u p-regulate major histocompatibility complex (MHC) class I transcriptio n were studied in two human hematopoietic tumor cell lines, K562 and R amos. These studies suggest that the IFN-gamma signal is transduced vi a an H7- and staurosporine-sensitive kinase that is distinct from prot ein kinase C (PKC) and protein kinase A (PKA) in both cell types. Ramo s cells appear to utilize an additional pathway involving double-stran ded RNA-dependent protein kinase. PKC and possibly PKA appear to be in volved in one or more intersecting pathways by which agonists of these kinases are able to act synergistically with IFN-gamma, but activatio n of these latter pathways is neither necessary nor sufficient for ind uction of MHC class I transcription. Modulation of G-protein- and Ca2-calmodulin-associated pathways and arachidonic acid metabolism had no effect on constitutive or IFN-gamma-stimulated class I transcription. The class I stimulatory factor produced in response to IFN-gamma trea tment appears to have a short t1/2. The identity of this factor is unk nown, but is likely to be distinct from known mediators of IFN-stimula ted transcription. Gene and cell-type specificity in the signal transd uction pathways utilized by IFN-gamma implies that such pathways may b e useful targets for experimental and therapeutic manipulation.