Effects of IL-8 Up-Regulation on Cell Survival and Osteoclastogenesis in Multiple Myeloma.
IL-8 promotes cancer cell growth, survival, angiogenesis, and metastasis in several tumors. Herein, we investigated the sources of IL-8 production in multiple myeloma (MM) and its potential roles in MM pathogenesis. We found that bone marrow cells from patients with MM secreted higher amounts of IL-8 than healthy donors. IL-8 production was detected in cultures of CD138(+) plasma cells and CD138(-) cells isolated from bone marrows of MM patients, and in three of seven human myeloma cell lines (HMCLs) analyzed. Interactions between MM and stromal cells increased IL-8 secretion by stromal cells through cell-cell adhesion and soluble factors. Interestingly, IL8 expression also increased in HMCLs, stromal cells, and osteoclasts after treatment with the antimyeloma drugs melphalan and bortezomib. In fact, the effect of bortezomib on IL-8 production was higher than that exerted by stromal-MM cell interactions. Addition of exogenous IL-8 did not affect growth of HMCLs, although it protected cells from death induced by serum starvation through a caspase-independent mechanism. Furthermore, IL-8 induced by stromal-MM cell interactions strongly contributed to osteoclast formation in vitro, because osteoclastogenesis was markedly reduced by IL-8-specific neutralizing antibodies. In conclusion, our results implicate IL-8 in myeloma bone disease and point to the potential utility of an anti-IL-8 therapy to prevent unwanted effects of IL-8 up-regulation on survival, angiogenesis, and osteolysis in MM.
Hematology Department, University Hospital of Salamanca, Biomedical Research Institute of Salamanca, Salamanca, Spain; Cancer Research Center, University of Salamanca, Salamanca, Spain.
Ana B
AB
Herrero
Bellvitge Biomedical Research Institute, Barcelona, Spain.
Antonio
A
García-Gómez
Hematology Department, University Hospital of Salamanca, Biomedical Research Institute of Salamanca, Salamanca, Spain; Cancer Research Center, University of Salamanca, Salamanca, Spain.
Mercedes
M
Garayoa
Hematology Department, University Hospital of Salamanca, Biomedical Research Institute of Salamanca, Salamanca, Spain; Cancer Research Center, University of Salamanca, Salamanca, Spain.
Luis A
LA
Corchete
Hematology Department, General Hospital of Segovia, Segovia, Spain.
José M
JM
Hernández
University Clinic of Navarra, Center of Applied Medical Research, Navarra Institute for Health Research, Pamplona, Spain.
Jesús
J
San Miguel
Hematology Department, University Hospital of Salamanca, Biomedical Research Institute of Salamanca, Salamanca, Spain; Cancer Research Center, University of Salamanca, Salamanca, Spain. Electronic address: normagu@usal.es.
Norma C
NC
Gutierrez
D002469:Cell Separation; D002470:Cell Survival; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D016133:Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D015854:Up-Regulation
C508606:CXCL8 protein, human; D016209:Interleukin-8