Granulocytes Negatively Regulate Secretion of Transforming Growth Factor beta 1 by Bone Marrow Mononuclear Cells via Secretion of Erythropoietin Receptors in the Milieu

In my previous study, I demonstrated that bone marrow-derived mononuclear cells (BM MNCs) secrete copious amounts of Transforming Growth Factor beta 1 (TGF beta 1) in response to erythropoietin (EPO). In this study, I investigated the principal cell type involved in the process. I found that a large percentage of various marrow cells, but not their mature counterparts present in the peripheral blood, express EPO-receptors (EPO-R). Cell depletion experiments showed that depletion of Glycophorin positive erythroblasts and CD41(+) megakaryocytes - the prime suspects - did not affect the EPO-mediated TGF beta 1 secretion by the BM MNCs. However, individual depletion of CD2(+) T lymphocytes, CD14(+) monocyte/macrophages, and CD19(+) B cells affected the TGF beta 1 secretion by EPO-primed MNCs: depletion of CD2(+) cells had the most striking effect. Unexpectedly, and most interestingly, depletion of CD15(+) granulocytes led to a significant increase in the TGF beta 1 secretion by both naive and EPO-primed BM MNCs, suggesting that these cells negatively regulate the process. Mechanistically, I show that the CD15(+) cells exert this regulatory effect via secretion of both full-length and soluble EPO-R in the milieu. Overall my results, for the first time, unravel an in-built regulatory mechanism prevailing in the BM microenvironment that regulates the secretion of TGF beta 1 by controlling EPO-EPO-R interaction. My data could be relevant in understanding the pathophysiology of several conditions associated with deregulated production of TGF beta 1 in the marrow compartment.

Automated summary

This study investigates the regulatory mechanism of TGF beta 1 secretion by bone marrow cells in response to erythropoietin, revealing that neutrophils negatively regulate this process by secreting EPO-R.