Interleukin-1 beta enhances and interferon-gamma 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-1beta (IL-1beta) and lipopolysaccharide (LPS), whereas interferon-gamma (IFN-gamma) inhibits the secretion of activin A by stromal fibroblasts. Concomitantly, IL-1beta as well as LPS inhibits and IFN-gamma 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-1beta 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-gamma on erythropoiesis is mediated at least in part by a suppression of activin A actions in bone marrow.
Abe
M
M
First Department of Internal Medicine, School of Medicine, University of Tokushima, Tokushima, Japan. masabe@clin.med.tokushima-u.ac.jp
Shintani
Y
Y
Eto
Y
Y
Harada
K
K
Fujinaka
Y
Y
Kosaka
M
M
Matsumoto
T
T
D028341:Activins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015672:Erythroid Precursor Cells / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism*; D038681:Follistatin; D006801:Humans; D028322:Inhibin-beta Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D017154:Stromal Cells / Q000166:cytology*
D016207:Cytokines; D038681:Follistatin; D007375:Interleukin-1; D012333:RNA, Messenger; C422405:activin A; D028341:Activins; D007371:Interferon-gamma; D028322:Inhibin-beta Subunits