Inadequate production of hematopoietic growth factors in hairy cell leukemia: up-regulation of interleukin 6 by recombinant IFN-alpha in vitro.
The course of hairy cell leukemia (HCL) is characterized by progressive pancytopenia. The pathogenesis of this phenomenon is still not fully understood. To study if the decrease in hematopoiesis in HCL is accompanied by abnormal concentrations of growth factors, we investigated the production of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin 3 (IL-3), interleukin 6 (IL-6), and tumor necrosis factor alpha by peripheral blood mononuclear cells (PBMCs) of eight patients with HCL. The results point to a severe deficiency of production of all cytokines tested as compared to healthy donors. However, enrichment of autologous monocytes by counterflow centrifugation resulted in a marked increase of the levels of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IL-6, and tumor necrosis factor alpha. The most pronounced effects were seen with IL-6. Reverse transcription-PCR analysis indicated that pokeweed mitogen, IFN-alpha, and poly(I:C) are capable of inducing the expression of IL-6-specific mRNA in HCL cells. These findings are substantiated on the protein level by immunofluorescence analysis. Incubation of PBMCs with IFN-alpha resulted in a significant increase of intracellular IL-6 in HCL but not in healthy donors. This increase was also seen in hairy cells positive for CD19 and CDllc. Furthermore, IFN-alpha induced the secretion of IL-6 from PBMCs of HCL patients but not healthy donors. In conclusion, our studies with PBMCs from patients with HCL revealed an inadequate supply of hematopoietic growth factors that might, in part, be due to the monocytopenia characteristic for this disease. The findings also indicate that IFN-alpha is capable of inducing the production of IL-6 in the patients' PBMCs as well as in their hairy cells. These data from our in vitro studies support the clinical observation that treatment with IFN-alpha leads to reconstitution of hematopoiesis.
Schwarzmeier
J D
JD
Department of Hematology, Clinic of Internal Medicine I, Ludwig-Boltzmann Institute for Cytokine Research, Vienna, Austria.
Hilgarth
M
M
Nguyen
S T
ST
Shehata
M
M
Gruber
G
G
Spittler
A
A
Willheim
M
M
Boltz-Nitulescu
G
G
Höcker
P
P
Berger
R
R
D000328:Adult; D000368:Aged; D018845:CD11 Antigens / Q000096:biosynthesis; D005260:Female; D016298:Hematopoietic Cell Growth Factors / Q000096:biosynthesis*; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007943:Leukemia, Hairy Cell / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D011043:Pokeweed Mitogens / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation
D018845:CD11 Antigens; D016298:Hematopoietic Cell Growth Factors; D016898:Interferon-alpha; D015850:Interleukin-6; D011043:Pokeweed Mitogens; D012333:RNA, Messenger