title: Induction of interleukin-8 expression in neuroblastoma cells by retinoic acid: implication of leukocyte chemotaxis and activation.
abstract: Neuroblastoma cells in response to retinoic acid (RA) exhibit differentiation. RA, which can promote tumor cell differentiation, has also been shown to regulate tumor-infiltrating leukocytes. In an attempt to explore the relationship between RA-induced neuroblastoma cell differentiation and leukocyte chemotaxis, we investigated expression of IL-1 beta, IL-8, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-alpha in the undifferentiated and RA-induced differentiated neuroblastoma cells. Using SK-N-SH neuroblastoma cells, we found that RA induced differentiation of SK-N-SH cells as demonstrated by down-regulation of N-myc gene expression, cell-cycle arrest in G1 phase, and phenotypic change. Neither RA-treated nor untreated neuroblastoma cells expressed IL-1 beta, granulocyte-macrophage colony stimulating factor, or tumor necrosis factor-alpha mRNA. RA-treated but not untreated SK-N-SH cells expressed IL-8 mRNA in a time- and dose-dependent fashion. As determined by ELISA, IL-8 levels were detectable in the culture supernatants from RA-treated, but not untreated, neuroblastoma cells (2.65 +/- 0.43 versus 0.05 +/- 0.04 ng/mL). Using neutrophil and lymphocyte chemotactic assays, we found that RA-treated but not untreated culture supernatants of neuroblastoma cells promoted neutrophil and lymphocyte chemotaxis. The RA enhancement of neuroblastoma cell-mediated leukocyte chemotaxis was significantly blocked by anti-IL-8 neutralizing antibodies. These results suggest that RA-induced neuroblastoma cell differentiation is associated with production of functional IL-8, which may be involved in the leukocyte infiltration and activation resulting in tumor regression.
authors.affiliation: Department of Pediatrics, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: K D
authors.initials: KD
authors.lastname: Yang
authors.forename: S N
authors.initials: SN
authors.lastname: Cheng
authors.forename: N C
authors.initials: NC
authors.lastname: Wu
authors.forename: M F
authors.initials: MF
authors.lastname: Shaio
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007375:Interleukin-1; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor