Toll-like receptor-1 (TLR-1) activation reduces immunoglobulin free light chain production by multiple myeloma cells in the context of bone marrow stromal cells and fibronectin

Abstract

Studies over the past years have provided evidence that Toll-like receptor (TLRs) activation in multiple myeloma (MM) cells induces heterogeneous functional responses including cell growth and proliferation, survival or apoptosis. These effects have been suggested to be partly due to increase in secretion of cytokines such as IL-6 or IFN among others from MM cells following TLR activation. However, whether triggering of these receptors also modulates production of immunoglobulin free light chains (FLCs) in MM cells has never been investigated. FLCs contribute largely to MM pathology. Here we explored the effect of TLR1 ligand (Pam3CSK4) alone or combined with bortezomib (BTZ) on production of FLCs in human myeloma cell lines, L363, OPM-2, U266 and NCI-H929 in the absence or presence of bone marrow stromal cells (BMSCs) or fibronectin (FN) to examine the influence of bone marrow microenvironment. Adhesion to BMSCs or FN increased secretion of FLC in MM cells. Pam3CSK4 decreased FLC production in the presence or absence of BMSCs or FN and this effect was enhanced in combination with BTZ. However, the level of reduction was lower in the presence of BMSCs or FN. Our findings imply that activation of TLR1 downregulates FLC production in MM cells even in the context of bone marrow microenvironment components and suggest that some TLRs such as TLR1 might be considered a therapeutic target especially in combined treatment protocols in MM.