title: Carcinoma-derived interleukin-8 disorients dendritic cell migration without impairing T-cell stimulation.
abstract: BACKGROUND
  Interleukin-8 (IL-8, CXCL8) is readily produced by human malignant cells. Dendritic cells (DC) both produce IL-8 and express the IL-8 functional receptors CXCR1 and CXCR2. Most human colon carcinomas produce IL-8. IL-8 importance in malignancies has been ascribed to angiogenesis promotion.
  
  
  RESULTS
  IL-8 effects on human monocyte-derived DC biology were explored upon DC exposure to recombinant IL-8 and with the help of an IL-8 neutralizing mAb. In vivo experiments were performed in immunodeficient mice xenografted with IL-8-producing human colon carcinomas and comparatively with cell lines that do not produce IL-8. Allogenic T lymphocyte stimulation by DC was explored under the influence of IL-8. DC and neutrophil chemotaxis were measured by transwell-migration assays. Sera from tumor-xenografted mice contained increasing concentrations of IL-8 as the tumors progress. IL-8 production by carcinoma cells can be modulated by low doses of cyclophosphamide at the transcription level. If human DC are injected into HT29 or CaCo2 xenografted tumors, DC are retained intratumorally in an IL-8-dependent fashion. However, IL-8 did not modify the ability of DC to stimulate T cells. Interestingly, pre-exposure of DC to IL-8 desensitizes such cells for IL-8-mediated in vitro or in vivo chemoattraction. Thereby DC become disoriented to subsequently follow IL-8 chemotactic gradients towards malignant or inflamed tissue.
  
  
  CONCLUSIONS
  IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation.
authors.affiliation: Gene Therapy and Hepatology Division, Centro de Investigación Médica Aplicada, Pamplona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Natalia
authors.initials: N
authors.lastname: Suárez
authors.forename: Ivan
authors.initials: I
authors.lastname: Martínez-Forero
authors.forename: Asís
authors.initials: A
authors.lastname: Palazón
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
authors.forename: Sarai
authors.initials: S
authors.lastname: Solano
authors.forename: Esperanza
authors.initials: E
authors.lastname: Feijoo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gúrpide
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolaños
authors.forename: Lorena
authors.initials: L
authors.lastname: Erro
authors.forename: Juan
authors.initials: J
authors.lastname: Dubrot
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Perez-Gracia
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000473:pathology* / Q000637:transplantation; D006801:Humans; D007267:Injections; D016209:Interleukin-8 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D002630:Chemotactic Factors; D016209:Interleukin-8