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-kappaB.

ABSTRACT

Toll 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-kappaB activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF-kappaB p65 and the activated NF-kappaB was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF-kappaB 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.