Abstract
BackgroundProduction of high levels of IL-6 is often correlated with resistance to cytotoxics or ionizing radiations, in cancer cell lines as in various cancer patients. We investigated whether monoclonal antibodies directed against IL-6 may enable to reverse resistance of cancer cell lines.Methodology/Principal FindingsWe exposed ten haematological cancer cells from lymphoma, myeloma, or leukemia origins to cytotoxics or ionizing radiations and assessed the effects of anti–IL-6 antibody addition on cell proliferation, apoptosis, or IL-6 signaling. A strong correlation between IL-6 secretion, measured by ELISA, and resistance to doxorubicin as ionizing radiations was observed in the multiple myeloma U266 and the Burkitt's lymphoma Daudi and Namalwa cells. Although an anti–IL-6 antibody combined to both treatments efficiently blocked IL-6 signaling in U266 cells, expressing the IL-6 receptor gp80, it did not increase treatment-induced anti-proliferative and pro-apoptotic effects on these cells, as well as on Daudi and Namalwa cells. This lack of effect could be related to diverse factors: 1) a higher release of the soluble form of IL-6 receptor gp80 in response to doxorubicin and irradiation from all cell lines, 2) an impaired level of the IL-6 pathway inhibitor SOCS3 in Daudi cells, and 3) an increased release of IL-10 and TNFα, two cytokines involved in cell radio- and chemoresistance.Conclusions/SignificanceThese data support the fact that IL-6 is not the preponderant actor of cell resistance to cytotoxics and ionizing radiations, which seems to be regulated by a complex network of proteins.
Highlights
Interleukin-6 (IL-6) is a key cytokine mainly produced by a broad variety of cell types including monocytes, fibroblasts, endothelial cells, and epithelial as haematological tumour cell lines [1]
IL-6 promotes the proliferation of haematological malignancies, and solid tumours [1,2], through an intracrine, autocrine and paracrine mode of action [3,4]
Tyrosine motifs in gp130 are crucial for recruitment of the feedback inhibitor SOCS3, which modulate IL-6 signaling via Jak inactivation and inhibition of STAT3/gp130 contact [12]
Summary
Interleukin-6 (IL-6) is a key cytokine mainly produced by a broad variety of cell types including monocytes, fibroblasts, endothelial cells, and epithelial as haematological tumour cell lines [1]. IL-6 promotes the proliferation of haematological malignancies (leukemia, lymphoma and myeloma), and solid tumours (breast and renal adenocarcinoma or Kaposi sarcoma) [1,2], through an intracrine, autocrine and paracrine mode of action [3,4]. A high IL-6 serum level is often associated to worse progression-free survival and overall survival in Non Hodgkin Lymphoma [5], myeloma [6], renal carcinoma and breast adenocarcinoma [7,8]. IL-6 binding results in gp130 dimerization and in the subsequent activation of Janus kinases, which activate in turn gp130 through phosphorylation of its intracellular domain. Production of high levels of IL-6 is often correlated with resistance to cytotoxics or ionizing radiations, in cancer cell lines as in various cancer patients. We investigated whether monoclonal antibodies directed against IL-6 may enable to reverse resistance of cancer cell lines
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