The effects of interleukin-1 beta and tumor necrosis factor-alpha on in vitro colony formation by human hematopoietic progenitor cells exposed to doxorubicin or hydroquinone.

Previous studies have shown that treatment of bone marrow (BM) cells with interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) can protect hematopoietic progenitor cells (HPC) from the toxic effects of 4-hydroperoxycyclophosphamide (4HC) or gamma-irradiation. Since doxorubicin (DX) and hydroquinone (HQ) may inhibit hematopoiesis through mechanisms similar to 4HC and gamma-irradiation, it was of interest to determine whether IL-1 beta or TNF-alpha could protect HPC from DX and HQ as well. Bone marrow mononuclear cells (BMMNC) or purified HPC (pHPC) were exposed to 50 ng/mL IL-1 beta or 25 ng/mL TNF-alpha alone or in combination with DX or HQ for 22 hours at physiological O2 partial pressure and temperature. The cells were washed free of the cytokines and toxicants and plated in cytokine-containing semisolid medium. Under these concurrent cytokine +/- toxicant treatment conditions, neither IL-1 beta nor TNF-alpha significantly affected progenitor cell frequencies (assessed as CFU-C) or lineage commitment compared with the medium-treated controls. Treatment with either 100 nM DX or 30 microM HQ, however, reduced CFU-C frequencies by approximately 70%. When BMMNC were used, treatment with neither IL-1 beta nor TNF-alpha consistently protected CFU-C from either DX or HQ. In contrast, using pHPC, IL-1 beta or TNF-alpha treatment conferred nearly two-fold protection of CFU-C from DX in all donors tested. TNF-alpha protected CFU-C from HQ using pHPC from all but one donor, while IL-1 beta did not protect CFU-C from HQ. Using phPC, maximum protection of CFU-C from DX was reached at IL-1 beta or TNF-alpha concentrations above 10 ng/mL or 1 ng/mL, respectively. Treatment of pHPC with TNF-alpha for at least 8 hours was necessary before significant protection from DX could be detected. Therefore, we conclude that IL-1 beta and TNF-alpha can act directly on human HPC to protect them from the inhibitory effects of DX and that, to a lesser extent, TNF-alpha can directly protect HPC from HQ.