ACTIVATION OF CYTOKINE PRODUCTION AND ADHESION MOLECULE EXPRESSION ONTHP-1 MYELOMONOCYTIC CELLS BY MACROPHAGE-COLONY-STIMULATING FACTOR INCOMBINATION WITH INTERFERON-GAMMA

THP-1 myelomonocytic leukemia cells cultured with either macrophage co lony-stimulating factor (M-CSF) or interferon-gamma (IFN-gamma) alone produce, at best, only low levels of interleukin-1 beta (IL-1 beta) an d tumor necrosis factor alpha (TNF-alpha), However, combinations of th e two factors resulted in at least 3- to 2O-fold greater amounts of IL -1 beta and TNF-alpha than would have been predicted by additive mecha nisms, This enhanced cytokine production was observed when M-CSF and I FN-gamma were added simultaneously or when M-CSF was added 24 h after addition of IFN-gamma to the cells, Similar results were obtained with fresh human peripheral blood cells treated with IFN-gamma + M-CSF. Cy cloheximide treatment of the cultures containing M-CSF and IFN-gamma i nhibited the production of IL-1 beta and TNF-alpha, Northern blotting studies revealed no effect of IFN-gamma alone on IL-1 beta or TNF-alph a mRNA production, IL-1 beta and TNF-alpha mRNA expression was observe d at 2 and 6 h after treatment with M-CSF or IFN-gamma + M-CSF. Higher TNF-a mRNA expression was observed at 2 and 6 h after treatment with IFN-gamma + M-CSF, and higher IL-1 beta mRNA expression was observed a t 2 h after treatment with IFN-gamma + M-CSF compared with mRNA levels observed for cells cultured only with M-CSF. These results suggest th at the augmented cytokine production resulting from treatments with co mbinations of M-CSF and IFN-gamma occurs due to increased cytokine mRN A and increased cytokine protein synthesis, In addition to up-regulati ng cytokines, combinations of IFN-gamma and M-CSF resulted in augmente d cell surface expression of intercellular adhesion molecule-1 and vas cular cell adhesion molecule-1, This was accompanied by morphological and functional changes that included plastic adherence, extensive homo typic aggregation, and a macrophagelike appearance, These phenotypic c hanges and enhancements in cytokine expression and cell surface molecu le expression may be related to activation of monocytic cells to becom e cytotoxic effecters by M-CSF and IFN-gamma combinations, In vitro cy totoxicity against A-375 melanoma cells was greatest for cultures that contained M-CSF and IFN-gamma in combination.