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Functional significance of novel neurotrophin‐1/B cell‐stimulating factor‐3 (cardiotrophin‐like cytokine) for human myeloma cell growth and survival
Author(s) -
Burger Renate,
Bakker Frank,
Guenther Andreas,
Baum Wolfgang,
SchmidtArras Dirk,
Hideshima Teru,
Tai YuTzu,
Shringarpure Reshma,
Catley Laurence,
Senaldi Giorgio,
Gramatzki Martin,
Anderson Kenneth C.
Publication year - 2003
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04686.x
Subject(s) - glycoprotein 130 , cancer research , cytokine , biology , janus kinase , tyrosine phosphorylation , stat3 , mapk/erk pathway , microbiology and biotechnology , signal transduction , medicine , endocrinology , immunology
Summary. Cytokines of the gp130 family, particularly interleukin 6 (IL‐6), play a central role in the growth and survival of malignant plasma cells. Recently, novel neurotrophin‐1 (NNT‐1)/B cell‐stimulating factor‐3 (BSF‐3), also reported as cardiotrophin‐like cytokine (CLC), was identified as a cytokine belonging to the gp130 family. BSF‐3, similar to IL‐6, exerts regulatory effects on normal B cell functions, but its functional significance in haematological malignancies has not been defined. The purpose of this study was to evaluate the biological effects and signalling pathways that are induced by BSF‐3 in malignant plasma cells. Recombinant human BSF‐3 was found to have growth stimulatory activity on plasmacytoma cell lines and primary tumour cells. In addition, BSF‐3 was able to protect from Dexamethasone (Dex)‐induced apoptosis. BSF‐3 stimulated cell growth could not be inhibited by neutralizing anti‐IL‐6 or anti‐IL‐6 receptor antibodies, but was abrogated by anti‐gp130 antibodies. In INA‐6.Tu11 cells, a subline of the IL‐6‐dependent human plasma cell line INA‐6 expressing gp130 and the receptor for leukaemia inhibitory factor (LIF), stimulation with BSF‐3 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). AG490, an inhibitor of Janus kinases, decreased BSF‐3 induced cell growth in a dose‐dependent manner. This correlated with a reduction of STAT3 phosphorylation levels, while p44/42 mitogen‐activated protein kinase (MAPK) phosphorylation was not affected. In conclusion, BSF‐3 is a novel myeloma growth and survival factor with a potential role in the pathophysiology of the disease.