Detection of functional and dimeric activin A in human marrow microenvironment. Implications for the modulation of erythropoiesis

• Published in: Annals of the New York Academy of Sciences 1994-04, Vol.718 (1), p.285-299
• Main Authors: Yu, A W, Shao, L E, Frigon, Jr, N L, Yu, J
• Format: Article
• Language: English
• Subjects: Activins; Base Sequence; Biological Assay; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow Cells; Cells, Cultured; Cytokines - pharmacology; DNA Primers; Enzyme-Linked Immunosorbent Assay; Erythropoiesis; Gene Expression; Growth Substances - analysis; Growth Substances - biosynthesis; Humans; Inhibins - analysis; Inhibins - biosynthesis; Macromolecular Substances; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger - analysis; RNA, Messenger - biosynthesis
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.1994.tb55727.x

Activin A, which was initially recognized as a gonadal protein, was implicated in the modulation of erythropoiesis through a paracrine control in the bone marrow microenvironment. Present studies demonstrate that, in contrast to T lymphocytes and cultured skin fibroblasts, human marrow stromal cells produce a functional and dimeric beta A beta A molecule (i.e., activin A). RT-PCR further indicates that both alpha and beta A mRNAs of inhibin A/activin A are produced in human stromal cells. The level of beta A subunit mRNAs, however, is in large excess over that of alpha subunit mRNAs, suggesting the predominant production of beta A beta A dimers, as well as some inhibin A (alpha beta A). It should be noted, however, that the beta A subunit can form dimeric proteins other than activin A, such as activin AB (beta A beta B) and inhibin A (alpha beta A). Hence, the presence of the beta A subunit may not necessarily indicate the production of the activin A molecule in any tissue. Therefore, a special quantitative sandwich ELISA assay specific for the dimeric beta A beta A molecule was developed for the measurement of activin A. With this assay, production of activin A in marrow stromal cells is found to be greatly enhanced by cytokines and inflammatory mediators such as TNF-alpha, IL-1 alpha, and lipopolysaccharide. These studies thus suggest that inflammatory cytokines are the inducers for activin A, probably serving a role of up-regulating activin A production locally in bone marrow microenvironment. At present, activin A is not known to play any role in inflammatory reaction; this study may thus raise the possibility that activin A performs more functions than are currently recognized. Alternatively, the enhanced production of this molecule in the bone marrow microenvironment may be regarded as a compensatory mechanism in host defenses, countering inflammatory mediators that are known to suppress erythropoiesis.