Transforming growth factor-beta1 affects interleukin-10 production in the bone marrow of patients with chronic idiopathic neutropenia.
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.
Pyrovolaki
Katerina
K
Department of Haematology, University of Crete School of Medicine, University Hospital of Heraklion, Heraklion, Crete, Greece.
Mavroudi
Irene
I
Papadantonakis
Nicolas
N
Velegraki
Maria
M
Ximeri
Maria
M
Kalpadakis
Christina
C
Gvazava
Gilda
G
Klaus
Mirjam
M
Eliopoulos
George D
GD
Papadaki
Helen A
HA
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*
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