Synergistic effect of IL-4 and TNF-α in the induction of monocytic differentiation of a mouse myeloid leukaemic cell line (WEHI-3B JCS)

We have previously shown that non-cytotoxic concentrations (600-1200 U/ml) of recombinant mouse tumour necrosis factor-α (TNF-α) can induce differentiation of a subclone (JCS) of the WEHI-3B myelomonocytic leukaemia cell line into mature cells with the characteristics of macrophages. In the present study, the effects of recombinant mouse interleukin-4 (IL-4), either alone or in combination with mouse TNF-α, on the growth and differentiation of JCS cells were examined. IL-4 alone (20 5000 U/ml) inhibited the growth of JCS cells in a dose-dependent manner but did not induce cell differentiation. However, combinations of IL-4 and TNF-α acted in synergy to inhibit cell proliferation and induce monocytic differentiation of JCS cells, as shown by increased expression of the macrophage differentiation antigens (F4/80, Mac- 1), stimulation of phagocytic activity, induction of non-specific esterase and NBT-reducing activities, increased plastic adherence and morphological criteria. Similar synergistic interactions were also shown by human TNF-α and mouse IL-4, indicating that TNF-α might exert its effects through the low-affinity (p55) TNF receptors. Moreover, the clonogenicity of JCS cells in vitro and their tumorigenicity in vivo were significantly reduced by combined TNF-α and IL-4 treatment. Our results indicate that TNF-α can act as a differential signal for JCS cells and that its effects are modulated by IL- 4. Therefore, the combination of TNF-α and IL-4 may be useful in the treatment of some forms of myelomonocytic leukaemia.