title: Transforming growth factor-beta1 affects interleukin-10 production in the bone marrow of patients with chronic idiopathic neutropenia.
abstract: BACKGROUND
  Chronic idiopathic neutropenia (CIN) is a bone marrow (BM) failure syndrome characterized by accelerated apoptosis of myeloid progenitor cells because of a local imbalance between pro-inflammatory and anti-inflammatory cytokines. In this study, we investigated the interplay among transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and soluble flt-3 ligand (sFL) within the BM of CIN patients and probed the role of these cytokines in the pathophysiology of CIN.
  
  
  METHODS
  We used long-term BM cultures (LTBMC) to evaluate TGF-beta1, IL-10, and sFL levels in CIN patients (n = 70) and healthy subjects (n = 35). Cytokine levels in LTBMC supernatants were correlated with the number of circulating neutrophils and the proportion of BM CD34+/CD33+ myeloid progenitor cells.
  
  
  RESULTS
  CIN patients had increased TGF-beta1 and sFL levels in LTBMCs compared with controls and individual cytokine values were found to be correlated inversely with the number of neutrophils and the proportion of CD34+/CD33+ cells. Patients displayed low supernatant IL-10 levels compared with controls and cytokine values were found to be correlated positively with the number of neutrophils and the proportion of CD34+/CD33+ cells. The levels of TGF-beta1 were found to be inversely correlated with IL-10 and positively with sFL values in LTBMC, supernatants suggesting a possible interplay among these cytokines in CIN BM. Neutralization of TGF-beta1 in LTBMCs increased IL-10 levels significantly in patients but not in controls, while neutralization had no effect on sFL levels.
  
  
  CONCLUSIONS
  Excessive production of TGF-beta1 within the BM microenvironment of CIN patients results in downregulation of IL-10 and reduction of myeloid progenitor cells. Overexpression of sFL probably represents a compensatory mechanism to the low myeloid progenitor cells.
authors.affiliation: Department of Haematology, University of Crete School of Medicine, University Hospital of Heraklion, Heraklion, Crete, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Pyrovolaki
authors.forename: Irene
authors.initials: I
authors.lastname: Mavroudi
authors.forename: Nicolas
authors.initials: N
authors.lastname: Papadantonakis
authors.forename: Maria
authors.initials: M
authors.lastname: Velegraki
authors.forename: Maria
authors.initials: M
authors.lastname: Ximeri
authors.forename: Christina
authors.initials: C
authors.lastname: Kalpadakis
authors.forename: Gilda
authors.initials: G
authors.lastname: Gvazava
authors.forename: Mirjam
authors.initials: M
authors.lastname: Klaus
authors.forename: George D
authors.initials: GD
authors.lastname: Eliopoulos
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis; D018952:Antigens, CD34 / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009503:Neutropenia / Q000097:blood* / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D016207:Cytokines; D008565:Membrane Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3; D053773:Transforming Growth Factor beta1; C084881:flt3 ligand protein; D016753:Interleukin-10