Lipoxygenase metabolites of arachidonic acid modulate hematopoiesis

Lipoxygenase (LPO) metabolites of arachidonic acid participate in the activation and/or proliferation of a variety of cell types. In this study, we examined the role of LPO metabolites in controlling myelopoiesis and erythropoiesis in vitro. Monocyte depleted cells (MDC) prepared from human whole blood or whole mononuclear cells from human bone marrow were cultured in methylcellulose in the presence of various growth factors. Conditioned media containing human colony stimulating factors (CSF) or the tumor-promoting phorbol ester, phorbol myristate acetate (PMA), were added to induce myelopoiesis. Semipurified human erythropoietin (EPO) was added along with an endogenous source of burst-promoting activity (BPA) to induce erythropoiesis. The LPO inhibitor BW755C blocked all types of colony formation in a dose-dependent manner, with ID50 of 20 and 5 micrograms/mL for myeloid and erythroid colonies, respectively. MDC depleted of T cells were similarly inhibited by BW755C. Similar results were seen with two other LPO inhibitors, 1-phenyl-3-pyrazolidone and butylated hydroxyanisole. A fourth LPO inhibitor, nordihydroguaiaretic acid, inhibited at higher concentrations. Indomethacin, at concentrations that inhibit cyclooxygenase, had no significant effect, either alone or in combination with the LPO inhibitors. These results suggest that certain LPO products may be important mediators of both CSF- and PMA-induced myelopoiesis, and of BPA/EPO-induced erythropoiesis.