Interleukin-6 leads to interleukin-10 production in several human multiple myeloma cell lines. Does interleukin-10 enhance the proliferation of these cells?
Introduction
Multiple myeloma (MM) is a haematological disorder of clonal malignant plasma cells that accounts for 1–2% of all human cancers. Many cytokines are involved in the growth and survival of these tumour cells [1], [2]. Interleukin-6 (IL-6) is an important cytokine in the proliferation of different multiple myeloma cells [3], [4]. IL-6 affects these tumour cells via autocrine and/or paracrine regulation mechanisms [3], [5]. It has been described that the signalling of IL-6 is mediated by the binding of IL-6 to its membrane-bound receptor (IL-6R). This complex could connect to the signal transducer membrane protein gp130, leading to an activation of JAKs/STAT and RAS/MAPKs pathways. Janus kinases (JAKs) and the signal transducer-activator of transcription (STAT) regulate survival, and RAS/mitogen-activated protein kinase (MAPK) is involved in the proliferation.
Interleukin-10 (IL-10) is produced mainly by TH2 cells, monocytes and B lymphocytes. It has been reported that three out of seven human myeloma cell lines produce IL-10 [6], which could affect the cells via gp130 related cytokines [7], [8]. Lu et al. [9] found that IL-10 is a proliferation factor for some MM cells, although in the absence of IL-6. Elevated IL-10 levels were detected in serum from about 50% of patients having multiple myeloma [7] showing a relation to the clinical manifestation of this disease [8].
It is known that cytokines interact with each other in a variety of ways: several are induced by common stimuli and different cells can produce the same cytokine. Cytokines can stimulate or inhibit synthesis or secretion of other cytokines. We asked (a) is IL-10 an IL-6 unrelated or a related growth factor for MM cells, i.e. is the production of IL-10 dependent on IL-6 or not? (b) Does IL-10 enhance the proliferation of myeloma cells? Therefore, we investigated ten multiple myeloma cell lines in an in vitro model. Six tumour cell lines were derived from blood, the others from ascitic fluid, bone marrow, peritoneum and lymph node.
Section snippets
Test substances
Recombinant human interleukin-6 (rh IL-6) and recombinant human interleukin-10 (rh IL-10) were obtained from R&D Systems (No. 206-IL and No. 1064-IL, United Kingdom) and reconstituted in phosphate-buffered saline with 0.18% bovine serum albumin. The IL-6 was calibrated with the NIBSC/WHO international standard (1 μg IL-6 is equivalent to 1.1 × 105 IU). Human interleukin-6 receptor antagonist (IL-6RA) was obtained from MedSystems (No. BMS 135, Diagnostics GmbH, Austria) and reconstituted in
Viability of tumour cells
The viabilities of control cells without test substances lay in the range of 71–95%. The test substances did not impair the viability of the cells.
Production of IL-10 in multiple myeloma cell lines
The IL-10 production of MM cells was measured without addition of IL-6 (spontaneous cytokine production), then 24 and 48 h after treatment with L-6 or with IL-6 receptor antagonist (IL-6RA). Table 1A presents the IL-10 production in pg/ml (range of 3–8 independent measurements). Spontaneous IL-10 production (up to 179 pg/ml) was found in 4/10 cell
Discussion
Multiple myeloma (MM) is characterised as a malignant plasma cell proliferation.
IL-6 is a major growth factor for malignant plasma cells and affects the cells mainly by an autocrine mechanism with additional paracrine signalling. It has been reported that IL-10 enhances the proliferation of malignant B cells as an autocrine growth (co)factor [10], [11], [12]. The elevated IL-10 serum level in multiple myeloma patients correlates with the progression of the disease [8], [13], suggesting that
Summary of the results
It is reported for the first time that exogenous IL-6 leads to a markedly increased IL-10 production in several human MM cell lines. With IL-6 receptor antagonist (IL-6RA) the values of IL-10 were in the range of untreated samples. In additional investigations IL-6RA counteracted the increased IL-10 production induced by IL-6 and decreased the high values of IL-10 significantly. IL-6 and IL-10 enhanced the proliferation of the MM cells. IL-10 is an IL-6 related factor in the proliferation of MM
Conflicts of interest
The idea of the study, presenting in this manuscript is based on the findings of the author. The Society of Cancer Research did not have any influence on the study planning, design and conduct. The Society was not interested in finishing of the investigations. The evaluation of the results, the writing and the completion of this manuscript were not supported from the Society of Cancer Research and from any foundation.
Acknowledgements
The author thanks Mrs. Dr. H. Langemann for the grammatical correction of this manuscript and Mrs. S. Link and Mrs. U. Toffol-Schmidt for the technical help. The measurements of the parameters were carried out in the laboratory of the Society of Cancer Research (Arlesheim, Switzerland) in relation to an experiment with two pharmaceutical substances.
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