Hematopoietic Rescue Via αl-Adrenoceptors on Bone Marrow B Cell Precursors and Endogenous Transforming Growth Factor-β
We demonstrated that adrenergic agents may affect hematopoiesis via high and low affinity al-adrenergic receptors present on bone marrow cells.1–3 Here we show that the high affinity, α 1-adrenoceptor is present on Macl-B220+sIgM- (pre-B) cells. Conversely, the low affinity α l-adrenoceptor seems to be present on Macl+B220- cells. Noradrenaline administration in mice rescued hematopoiesis from the toxic effect of carboplatin or X-rays sublethal irradiation. The protection was reflected by higher leukocyte and platelets counts as well as by increased bone marrow granulocyte/macrophage colony-forming units (GM-CFU). At its most effective dose (3 mg/ kg, s.c.), noradrenaline protected 77% of the mice injected i.v. with 200 mg/ kg of carboplatin (LD 100: 170 mg/kg) but not mice which were lethally irradiated (900cGy). In vitro, noradrenaline (1 μM) rescued GM-CFU in unseparated bone marrow cells containing the adherent population expressing the high affinity α 1-adrenoceptor, but not in non-adherent cells containing the low affinity receptor. Consistently, the hematopoietic rescue was counteracted by low concentrations (0.1 nM-10 nM) of the α l-antagonist prazosin. Anti-trans-forming growth factor-β (TGF- β) monoclonal antibodies prevented the hematopoietic rescue exerted by noradrenaline. This suggests that activation of al-adrenoceptor on pre-B cell results in production of endogenous TGF- β. Our findings describe a novel mechanism of hematopoietic regulation and might find application in preventing the myeloablative effect of anti-cancer treatments.
KeywordsToxicity Lymphoma Leukemia Fractionation Doxorubicin
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