TLR5 activation by flagellin induces doxorubicin resistance via interleukin-6 (IL-6) expression in two multiple myeloma cells.
Multiple myeloma (MM) is an incurable B-cell hematologic malignancy characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM cells interact with various cells within the BM microenvironment, leading to skeletal destruction, angiogenesis, and drug resistance. Therefore, control of the cell-host interaction and growth factors is important to improve patient outcome with conventional treatments. In this study, we investigated flagellin-induced cell proliferation, cytokines expression, and the mechanisms of cancer drug resistance that lead to the failure of cytotoxic therapies for MM. The human MM line KMS28BM expresses the TLR5 gene as well as the protein at high levels. When treated with the specific TLR5 ligand flagellin, KMS28BM cells showed increased proliferation, increased IgG λ production, and high-level expression and secretion of the pro-inflammatory cytokine IL-6, via NF-κB activation through p38 and PI3K/AKT signaling. Furthermore, flagellin-stimulated KMS28BM cells were shown to have "increased doxorubicin and apoptosis resistance" through the inhibition of caspases and PARP activity, and this result was reversed by blocking IL-6. Thus, increased cell viability and the chemoresistance of flagellin-stimulated KMS28BM cells may result from autocrine or paracrine signaling mediated by secreted IL-6. These findings indicate that TLR5 activation by flagellin may elicit chemoresistance in MM patients who have suffered from recurrent bacterial infections.
Advanced Research Center for Multiple Myeloma, Busan 614-735, Republic of Korea; Department of Microbiology and Immunology, Busan 614-735, Republic of Korea.
Hae-Yun
HY
Cho
Advanced Research Center for Multiple Myeloma, Busan 614-735, Republic of Korea; Department of Microbiology and Immunology, Busan 614-735, Republic of Korea; Bio-Marker Research Center for Personalized Therapy, College of Medicine, College of Medicine, Inje University, Busan 614-735, Republic of Korea. Electronic address: swlee@inje.ac.kr.
Soo-Woong
SW
Lee
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005408:Flagellin / Q000276:immunology* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D009101:Multiple Myeloma / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; C508600:IL6 protein, human; D007074:Immunoglobulin G; D015850:Interleukin-6; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
Doxorubicin; Flagellin; IL-6; Multiple myeloma; TLR5