Interleukin‐1 β enhances and interferon‐γ suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts
Activin A is a multi‐functional cytokine with a potent stimulation on erythroid cell differentiation in the bone marrow. The actions of activin A are determined by a balance of the levels of activin A and its inhibitor, follistatin (FS). However, the regulation of its actions in the bone marrow has been unclear. Here we show that bone marrow‐derived stromal fibroblasts are the major source of activin A and FS in the bone marrow, and that the production of activin A is enhanced by interleukin‐1β (IL‐1β) and lipopolysaccharide (LPS), whereas interferon‐γ (IFN‐γ) inhibits the secretion of activin A by stromal fibroblasts. Concomitantly, IL‐1β as well as LPS inhibits and IFN‐γ stimulates FS secretion from stromal fibroblasts. Thus, these cytokines potently regulate activin A actions by reciprocal modulation of activin A and FS secretion from stromal fibroblasts. Because activin A exhibits anti‐inflammatory effects in various tissues, up‐regulation of activin A actions by IL‐1β and endotoxin in the bone marrow may play a protective role against inflammatory processes as well as anaemia. The present results also suggest that the inhibitory effect of IFN‐γ on erythropoiesis is mediated at least in part by a suppression of activin A actions in bone marrow.