title: Role of interleukin 16 in multiple myeloma.
abstract: BACKGROUND
  Multiple myeloma is a malignancy characterized by the expansion of a plasma cell clone that localizes to the human bone marrow. Myeloma cells and bone marrow stromal cells produce soluble factors that promote the survival and progression of multiple myeloma. Interleukin 16 (IL-16) is involved in regulating the migration and proliferation of normal leukocytes. However, the role of IL-16 in human cancers, including multiple myeloma, is unclear.
  
  
  METHODS
  We investigated IL-16 expression in cell lines (n = 10) and in the bone marrow of myeloma patients (n = 62) and healthy bone marrow donors (n = 12) by quantitative reverse transcription-polymerase chain reaction, immunoblot analysis, enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemistry. Transfection of two human multiple myeloma cell lines with small interfering RNAs was used to examine the effect of IL-16 gene silencing on apoptosis by flow cytometry, on proliferation by bromodeoxyuridine incorporation, and on colony formation. Protein neutralization assays were performed by treating multiple myeloma cells with a monoclonal antibody against the carboxyl-terminal fragment of IL-16. All statistical tests were two-sided.
  
  
  RESULTS
  IL-16 was strongly overexpressed in the bone marrow of myeloma patients compared with healthy donors. Myeloma cell lines as well as primary tumor cells from myeloma patients constitutively expressed IL-16 and its receptors CD4 and/or CD9 and spontaneously secreted soluble IL-16. Silencing of IL-16 reduced the proliferative activity of myeloma cells by approximately 80% compared with untreated cells (mean relative proliferative activity IL-16 siRNA vs untransfected cells, EJM cells: 20.1%, 95% confidence interval [CI] = 14.3% to 26.0%, P = .03; KMS-12-BM cells: 22.8%, 95% CI = 5.5% to 40.0%, P = .04), and addition of a recombinant carboxyl-terminal IL-16 peptide reversed that effect. A monoclonal antibody directed against IL-16 or its receptors had a comparably strong growth-inhibiting effect on the tumor cells.
  
  
  CONCLUSIONS
  IL-16 is an important growth-promoting factor in multiple myeloma and a candidate for novel diagnostic, prognostic, and therapeutic applications for this incurable human malignancy.
authors: Department of Medicine II, Oncology/Hematology/Stem Cell Transplantation, University Cancer Center Hamburg (Hubertus Wald Tumorzentrum), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. d.atanackovic@uke.uni-hamburg.de
authors: Djordje
authors: D
authors: Atanackovic
authors: York
authors: Y
authors: Hildebrandt
authors: Julia
authors: J
authors: Templin
authors: Yanran
authors: Y
authors: Cao
authors: Christiane
authors: C
authors: Keller
authors: Jens
authors: J
authors: Panse
authors: Sabrina
authors: S
authors: Meyer
authors: Henrike
authors: H
authors: Reinhard
authors: Katrin
authors: K
authors: Bartels
authors: Nesrine
authors: N
authors: Lajmi
authors: Orhan
authors: O
authors: Sezer
authors: Axel R
authors: AR
authors: Zander
authors: Andreas H
authors: AH
authors: Marx
authors: Ria
authors: R
authors: Uhlig
authors: Jozef
authors: J
authors: Zustin
authors: Carsten
authors: C
authors: Bokemeyer
authors: Nicolaus
authors: N
authors: Kröger
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000378:metabolism; D060245:Tetraspanin 29 / Q000378:metabolism; D015854:Up-Regulation; D019410:Interleukin-16 / Q000235:genetics / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; C554869:CD9 protein, human; D034741:RNA, Small Interfering; D060245:Tetraspanin 29; D019410:Interleukin-16