title: Interleukin-4 adenoviral gene therapy reduces production of inflammatory cytokines and prostaglandin E2 by rheumatoid arthritis synovium ex vivo.
abstract: BACKGROUND
  The rheumatoid arthritis (RA) joint is characterized by an inflammatory synovial pannus which mediates tissue destruction. Interleukin (IL)-4 reduces the production of many proinflammatory cytokines, particularly by activated macrophages. Therefore, we examined the ability of adenovirally delivered IL-4 for the treatment of human RA to reduce the secretion of proinflammatory molecules.
  
  
  METHODS
  Adenoviral vectors encoding the genes for human IL-4 (AxCAIL-4) and bacterial beta-galactosidase (AxCAlacZ) were generated and examined for appropriate production and biological activity. RA synovial tissue (ST) explants or fibroblasts were infected with AxCAIL-4 or a beta-galactosidase producing vector, as a control, and conditioned medium (CM) was collected for ELISA analysis.
  
  
  RESULTS
  AxCAIL-4 decreased the production of the inflammatory cytokines IL-1 beta and tumor necrosis factor-alpha in RA ST explant CM. IL-8 levels were significantly reduced by 71%, 88%, and 82% at 24, 48, and 72 hours, respectively, in RA ST explant CM. In the same CM, monocyte chemotactic protein-1 (MCP-1) levels decreased 60% at 48 hours. In contrast, RA synovial fibroblast CM levels of MCP-1 were increased by AxCAIL-4. Epithelial neutrophil activating peptide-78 levels produced by RA ST explants were significantly decreased by AxCAIL-4 by 88%, 92%, and 93% at 24, 48, and 72 hours, respectively. Growth related gene product-alpha levels were likewise decreased in RA ST explant CM. In ST explants as well as RA synovial fibroblasts, IL-4 treatment decreased prostaglandin E2 (PGE2) production.
  
  
  CONCLUSIONS
  Increased expression of IL-4 via gene therapy may decrease RA-associated inflammation by reducing proinflammatory cytokines and PGE2.
authors.affiliation: Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Woods
authors.forename: M
authors.initials: M
authors.lastname: Tokuhira
authors.forename: J C
authors.initials: JC
authors.lastname: Berry
authors.forename: K J
authors.initials: KJ
authors.lastname: Katschke
authors.forename: H
authors.initials: H
authors.lastname: Kurata
authors.forename: J A
authors.initials: JA
authors.lastname: Damergis
authors.forename: K
authors.initials: K
authors.lastname: Arai
authors.forename: A E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000378:metabolism* / Q000821:virology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D015847:Interleukin-4; D001616:beta-Galactosidase; D015232:Dinoprostone