Rapamycin antagonizes interleukin-6 mediated growth arrest and differentiation of myeloblastic M1 cells

The immunosuppressant rapamycin is known to be a potent inhibitor of cytokine driven proliferation of T-lymphocytes and other cell types. Here we have examined the effect of rapamycin on the myeloblastic cell line M1 which responds to interleukin-6 (IL-6) with growth arrest and monocytoid differentiation. Single-agent rapamycin led to a retardation of M cell growth. In spite of this intrinsic antiproliferative effect, rapamycin was found to abrogate IL-6 induced growth arrest. Concomitant exposure to rapamycin and IL-6 also reduced the extent of monocytoid differentiation as compared to treatment with IL-6 alone. Excess levels of the FK-506 analogue ascomycin reversed the antagonistic effect of rapamycin on IL-6 mediated growth suppression, suggesting that this biological action of rapamycin is mediated by a rapamycin/immunophilin complex. The findings demonstrate that rapamycin can also act as an antagonist of cytokine induced growth arrest and differentiation.