COMPARATIVE-ANALYSIS OF CYTOKINES RELEASED BY BONE-MARROW STROMAL CELLS FROM NORMAL DONORS AND B-CELL CHRONIC LYMPHOCYTIC LEUKEMIC PATIENTS

We studied the production of cytokines (G-CSF, GM-CSF, IL-6, LIF and I L-10) by bone marrow stromal cells of five untreated patients with B-C LL, in Rai stage 0, I and II, and of 8 healthy subjects. The productio n of G-CSF, GM-CSF, LIF and IL-10 did not differ significantly between controls and B-CLL patients. However, the ability of stromal cells to release IL-6 in response to LPS was decreased in all patients: 36 +/- 5 ng/m/versus 123 +/- 47 ng/ml for normal controls (p < 0.004). Moreo ver, a soluble activity that inhibited hematopoietic colony formation was detected in B-CLL stromal cell conditioned media. Some potential i nhibitors were envisaged and the results indicated an increased produc tion of TGF-beta by B-CLL stromal cells compared to normal stromal cel ls (respectively 53 +/- 10 versus 15 +/- 4 ng/ml, p < 0.03). The reduc ed capacity of B-CLL stromal cells to produce IL-6 was associated with this excessive release of TCF-beta; indeed, addition of anti-TGF-beta neutralizing antibody to B-CLL stromal cells, before LPS stimulation, totally normalized the production of IL-6. TGF-beta and IL-6 were als o measured in serum samples from normal subjects and B-CLL patients. N o significant difference was seen in the production of total TGF-beta (bioactive and latent forms) between normal and B-CLL sera but the mea n level of bioactive protein in B-CLL sera was increased in comparison with normal sera (1.74 +/- 0.44 versus 0.67 +/- 0.2 ng/ml, p < 0.04). Furthermore, low serum levels of IL-6 were found in normal and B-CLL sera but detectable levels of IL-6 were less frequent in B-CLL sera. I n conclusion, in B-CLL, decreased IL-6 production by stromal cells and inhibiting activity on hematopoietic progenitors are attributable to increased production of TGF-beta. This increased amount of TGF-beta is also seen in sera of B-CLL patients. Our report supports the hypothes is that overproduction of TGF-beta could play a pathogenic role in som e manifestations of this disease such as bone marrow failure, deficien cy in platelet and Ig production.