Stimulation of MHC Class I Transcription by Interferon-γ Involves a Non-A,Non-C Kinase in Addition to Protein Kinase C

Abstract

The signal pathways by which interferon-γ (IFN-γ) is able to up-regulate major histocompatibility complex (MHC) class I transcription were studied in two human hematopoietic tumor cell lines, K562 and Ramos. These studies suggest that the IFN-γ signal is transduced via an H7- and staurosporine-sensitive kinase that is distinct from protein kinase C (PKC) and protein kinase A (PKA) in both cell types. Ramos cells appear to utilize an additional pathway involving double-stranded RNA-dependent protein kinase. PKC and possibly PKA appear to be involved in one or more intersecting pathways by which agonists of these kinases are able to act synergistically with IFN-γ, but activation of these latter pathways is neither necessary nor sufficient for induction 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-γ-stimulated class I transcription. The class I stimulatory factor produced in response to IFN-γ treatment appears to have a short t _½. The identity of this factor is unknown, but is likely to be distinct from known mediators of IFN-stimulated transcription. Gene and cell-type specificity in the signal transduction pathways utilized by IFN-γ implies that such pathways may be useful targets for experimental and therapeutic manipulation.