Low frequency of myeloid progenitor cells in chronic idiopathic neutropenia of adults may be related to increased production of TGF‐β1 by bone marrow stromal cells

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Abstract
Previous studies in our laboratory have shown that patients with chronic idiopathic neutropenia of adults (CINA) have increased serum levels of inflammatory cytokines including IL-1β. Since IL-1β may affect bone marrow stromal cell function, a study was designed to investigate the capacity of patients' stromal cells to produce adequate amounts of haemopoietic growth factors or excessive amounts of inhibitors of myelopoiesis in long-term bone marrow cultures (LTBMCs). The study was carried out on 52 CINA patients and 19 normal controls. We found that CINA patients had significantly low numbers of marrow lineage-specific CD34+ cells, including CFU-GM and CD34+/CD33+ cells. Stromal cells from patients' LTBMCs failed to stimulate CFU-GM colony formation by normal marrow cells in a manner comparable to that of stromal cells of controls. Patients' LTBMC supernatants had normal or increased amounts of G-CSF. Detectable amounts of supernatant GM-CSF were found in 35% of patients and 19% of controls. IL-3 and MIP-1α were not detected in any supernatant fluid. Moreover, supernatants from patients' LTBMCs had increased concentrations of IL-6 and TGF-β1, which strongly correlated with serum IL-1β. About 82% of our patients had TGF-β1 values higher than the upper limit of values found in the controls. Individual TGF-β1 values inversely correlated with the number of circulating neutrophils and the frequency of marrow CD34+/CD33+ cells. We suggest that increased levels of serum IL-1β, resulting from an underlying low-grade chronic inflammatory process, may stimulate marrow stromal cells to produce both haemopoietic growth factors and inhibitors of myelopoiesis. Since steady-state myelopoiesis results from a balance between negative- and positive-acting cytokines, it seems very probable that the increased production of TGF-β1 by bone marrow microenvironment in CINA patients may suppress myelopoiesis and contribute, to some extent, to the pathogenesis of neutropenia in affected subjects.