Synergistic interactions of interleukin 1, interferon-beta, and tumor necrosis factor in terminally differentiating a mouse myeloid leukemic cell line (M1) . Evidence that interferon-beta is an autocrine differentiating factor
Onozaki, K.; Urawa, H.; Tamatani, T.; Iwamura, Y.; Hashimoto, T.; Baba, T.; Suzuki, H.; Yamada, M.; Yamamoto, S.; Oppenheim, J.J.
Journal of Immunology 140(1): 112-119
1988
ISSN/ISBN: 0022-1767 PMID: 3275716 Document Number: 319852
The effect was investigated of combinations of cytokines known to be cytostatic for some tumor cells, namely interleukin 1.alpha. (IL-1.alpha.), interferon-.beta. (IFN-.beta.), and tumor necrosis factor (TNF), on the growth and differentiation of the mouse myeloid leukemic cell line, M1, cells. IL-1.alpha., IFN-.beta., and TNF by themselves are antiproliferative for M1 cells. Treatment of cells with a mixture of any two of the three cytokines resulted in at least additive growth inhibition. None of these cytokines by themselves induced differentiation of M1 cells as assessed by increased expression of Fc receptors (FcR), stimulation of phagocytic activity and by morphologic criteria. However, as little as 1 U/ml IL-1.alpha. in conjunction with IFN-.beta. or TNF increased FcR expression, phagocytic activity and morphologic changes in addition to inhibiting the growth of M1 cells. The combination of IFN-.beta. and TNF did not induce differentiation, although the growth of the cells was markedly inhibited. Both TNF and lipopolysaccharide (LPS) induced the in vitro production of IFN activity by M1 cells. Furthermore, the induction of differentiation of M1 cells by a combination of IL-1.alpha. with either IFN-.beta., TNF, or LPS was inhibited by antibody against mouse IFN-.beta. Therefore, it appears that IFN-.beta. provides one of the two required signals for differentiation of M1 cells by these combinations of stimulants, the other being IL-1. Furthermore, the cytostatic effect of TNF by itself on M1 cells was also partly blocked by anti-IFN-.beta. antibody, suggesting that IFN-.beta. is also involved in the growth inhibitory effect of TNF for M1 cells. In contrast, the cytostatic effect of IL-1 on M1 cells was not blocked by anti-IFN-.beta. antibody. In conclusion, both the cytostatic and differentiative effect of TNF appear to be mediated by IFN-.beta. Thus, the combination of IL-1 and IFN-.beta. or inducers of IFN-.beta. resulted in terminal differentiation of M1 cells. Northern blot analysis using cDNAs for murine IFN-.beta.1 or human IFN-.beta.2 showed an increased expression of mRNA for IFN-.beta.1 but not for IFN-.beta.2 by stimulation with TNF or LPS, strongly suggesting that IFN-.beta.1 rather than IFN-.beta.2 is responsible for TNF or LPS effects.