Expression and function of toll‐like receptors in multiple myeloma patients: toll‐like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor‐κB

Abstract

SummaryToll like receptors (TLRs) are the major agents for innate immunity that recognize invading microbial products and regulate the growth of normal and malignant human B lymphocytes. Multiple myeloma (MM) is a clonal plasma cell malignancy, though the regulatory role of TLRs in MM plasma cells has been reported, the molecular mechanism remains unclear. We first compared the transcripts of TLR1 to TLR10 in MM patients and healthy donors and found that TLR2, ‐4 and ‐9 transcripts were higher in bone marrow mononuclear cells (BMMCs) from patients than those from donors; in addition the expression of TLR4 and TLR9 were higher in MM cells than normal cells as demonstrated by flow cytometric analyses. The ligands of these two TLRs were capable to promote the growth of MM cells and protect them from serum‐deprivation‐induced apoptosis but not normal plasma cells, which could be attenuated with anti‐IL6 neutralizing antibodies or blockage of NF‐κB activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF‐κB p65 and the activated NF‐κB was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF‐κB signalling probably plays a crucial role for the ligands of TLR4 and TLR9 to promote the growth and survival of MM cells partially through IL6 autocrine.

Phosphorothioate modification of the TLR9 ligand CpG ODN inhibits poly(I:C)-induced apoptosis of hepatocellular carcinoma by entry blockade

“…Due to the pivotal role of TLRs in immune responses to pathogens, substantial research has been carried out with the aim of understanding the function and biological importance of TLRs on immune cells. However, TLRs are also expressed on many kinds of tumors, such as on melanoma, brain tumor and colon tumor cells [4][5][6][7][8]. Preliminary evidence has suggested that TLRs expressed on tumor cells may play an important role in tumor development.…”

Epigenetic Regulation of Toll-Like Receptor Signaling: Implications for Cancer Development

“…In the case of mantle cell lymphoma, stimulation of TLR4 by LPS promoted tumor growth and played an imparting role in the resistance of cytotoxic T lymphocyte-mediated destruction [67]. MMs also use TLR4 in malignant progression, promoting proliferation in part by the proliferative abilities mediated by IL-6 production, preventing apoptosis and facilitating immune evasion [68,69,70]. To some extent, TLR9 may play a role in such progression as well [68].…”

Prognostic Value of Genetic Markers for Efficacy Estimation of Induction Treatment Including Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients

“…J. Bohnhorst и соавт. [107] обнаружили TLR-опосредованные взаимодействия между ними [108]. Механизмы этой взаимосвязи не до конца понятны, хотя утверждается, что прогрессирование ММ иници-ируется в местах воспаления [109].…”

“…Активация TLR опосредует секрецию аутокринного IL-6 стромальными клетками костного мозга. IL-6 является самым важным фактором роста Значение генетических маркеров при ММ и выживания клеток ММ [107,111], участвующим в формировании лекарственной устойчивости [105].…”

“…Исследования при ММ, проведенные ранее, по-зволили выявить, что стимуляция TLR на клетках ММ соответствующими лигандами усиливает их устой-чивость к действию дексаметазона, а также способ-ствует росту и пролиферации [107,111]. Погибающие в результате цитотоксической терапии опухолевые клетки вызывают развитие противоопухолевого им-мунного ответа посредством высвобождения HMGB1 и других эндогенных лигандов, таких как нуклеиновые кислоты, связывающиеся с TLR4 [123].…”