CORRELATED SUSCEPTIBILITY BETWEEN INTERFERON-BETA AND UV IN HUMAN CELL-LINES, F-IFR AND RSA - IMPLICATION OF UNIFYING ANTIPAIN-SENSITIVE MECHANISMS FOR BOTH STIMULI

The human cell line F-IFr is a variant with an increased resistance to cell proliferation inhibition (CPI) by human interferon (HuLFN)-beta, established from RSa cells with high sensitivity to CPI. The parent R Sa cells were recently found to be unusually hypermutable after irradi ation with far-ultraviolet light (UV), as assessed by two different me thods; estimation of the cloning efficiency of ouabain-resistant (Oua( R)) mutants and detection of K-ras codon 12 mutation in genomic DNA id entified by polymerase chain reaction following differential dot blot hybridization. In the present study, F-IFr cells were found to be hypo mutable; less than one Oua(R) mutant per 10(4) survival cells after UV (0-12 J/m(2)), in contrast to 0.51-85 Oua(R) mutants per 10(4) surviv ors in RSa cells, and no detectable K-ras codon 12 mutation at any UV dose tested. However, F-IFr cells, when cultured with medium containin g the protease inhibitor antipain immediately and transiently after UV irradiation displayed hypermutability to almost the same extent as RS a cells by both phenotypic and genetic mutation analyses. The refracto riness of F-IFr cells to HuIFN-beta CPI was also suppressed by culture with medium containing antipain during HuIFN-beta exposure. Moreover, F-IFr cells irradiated with UV or treated with HuIFN-beta showed elev ation of antipain-sensitive protease activity, but not the irradiated or treated RSa cells. UV- and HuIFN-beta-susceptibility were not modul ated by antipain in RSa cells. These antipodal characteristics between the two cell lines suggested that antipain-sensitive proteases and/or cellular functions may be involved in increased resistance of F-IFr c ells to both Wand HuIFN-beta refractoriness.