ARE LIF AND RELATED CYTOKINES FUNCTIONALLY EQUIVALENT

Leukemia inhibitory factor (LIF) is structurally related to interleuki n-6 (IL-6), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) . Since LIF-deficient mice do not exhibit overt phenotypic effects in cell types known to be targets for LIF action in vitro, we examined th e ability of IL-6, OSM, and CNTF to reproduce the effects of LIF in fi ve different bioassays. OSM, CNTF, and LIF are able to promote embryon ic stem cell growth and to maintain them in an undifferentiated state as marked by a high alkaline phosphatase activity (ED(50) are, respect ively, 0.5, 3 and 1 ng/ml). Whereas LIF and OSM maintain close to 100% of ES cells in an undifferentiated state, CNTF, at optimal concentrat ions, prevents differentiation of only 60% of the ES population. Murin e 7TD1 hybridoma cell growth is induced only in the presence of IL-6 ( ED(50) = 0.1 ng/ml). Both LIF and OSM stimulate DA1a cell proliferatio n (ED(50) are, respectively, 1 and 12 ng/ml). OSM appears, therefore, to act as a weak agonist of LIE-dependent processes on murine cells, h owever, with a 10-fold lower specific activity than that of LIF, which is in agreement with human OSM cross-reacting with the murine LIF-R. Though IL-6, LIF, and OSM all stimulate haptoglobin and fibrinogen pro duction by human HepG2 hepatoma cells, the dose-response curves of the se three factors exhibit very different characteristics. CNTF stimulat es acute-phase protein production by HepG2 cells only at high concentr ations (greater than 1 mu g/ml). A549 epithelial cells are subjected t o growth inhibition only in the presence of OSM (ED(50) = 6 ng/ml), ev en though they expressed LIF-R and gp130 transcripts. These data sugge st that OSM and LIF act on human cells through different receptors. Al together, these results indicate that none of the factors examined in this study are precisely interchangeable in terms of their biological actions. (C) 1994 Academic Press, Inc.