TGF-beta1 induces bone marrow reticulin fibrosis in hairy cell leukemia.
The mechanisms that lead to reticulin fibrosis of bone marrow (BM) in hairy cell leukemia (HCL) are not fully understood. We therefore investigated the involvement of TGF-beta1, a potent fibrogenic cytokine, in this process. Immunoassays revealed that TGF-beta1 is present at higher concentrations in BM, serum, and plasma of HCL patients in comparison with healthy donors (P < 0.001). RT-PCR and immunofluorescence studies showed that TGF-beta1 is overexpressed at the mRNA and protein levels in peripheral blood, spleen, and BM mononuclear cells and that hairy cells (HCs) are the main source of TGF-beta1. Active TGF-beta1 correlated significantly with grades of BM fibrosis, infiltration with HCs, and serum procollagen type III aminoterminal propeptide (PIIINP). Ex vivo studies demonstrated that TGF-beta1 significantly enhances the production and deposition of reticulin and collagen fibers by BM fibroblasts. In addition, BM plasma of HCL patients increased the synthesis of type I and type III procollagens, the main components of reticulin fibers, at the mRNA and protein levels. This fibrogenic activity of BM plasma was abolished by neutralizing anti-TGF-beta1 antibodies. These results show, for the first time to our knowledge, that TGF-beta1 is highly expressed in HCs and is directly involved in the pathogenesis of BM reticulin fibrosis in HCL.
Department of Hematology, Clinic of Internal Medicine I, Vienna, Austria.
Medhat
M
Shehata
Josef D
JD
Schwarzmeier
Martin
M
Hilgarth
Rainer
R
Hubmann
Markus
M
Duechler
Heinz
H
Gisslinger
D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024061:Collagen Type III / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007118:Immunoassay; D007943:Leukemia, Hairy Cell / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry; D055728:Primary Myelofibrosis / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D012155:Reticulin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D024061:Collagen Type III; D010455:Peptides; D012333:RNA, Messenger; D012155:Reticulin; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen