Low frequency of myeloid progenitor cells in chronic idiopathic neutropenia of adults may be related to increased production of TGF-beta1 by bone marrow stromal cells.

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-1beta. Since IL-1beta 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-1alpha were not detected in any supernatant fluid. Moreover, supernatants from patients' LTBMCs had increased concentrations of IL-6 and TGF-beta1, which strongly correlated with serum IL-1beta. About 82% of our patients had TGF-beta1 values higher than the upper limit of values found in the controls. Individual TGF-beta1 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-1beta, 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-beta1 by bone marrow microenvironment in CINA patients may suppress myelopoiesis and contribute, to some extent, to the pathogenesis of neutropenia in affected subjects.