title: Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis.
abstract: BACKGROUND
  Sargramostim, granulocyte macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Clinical trials show that sargramostim induces clinical response and remission in patients with active Crohn's disease. To study the mechanism, we examined the effects of GM-CSF in the dextran sulfate sodium (DSS)-induced acute colitis model. We hypothesized that GM-CSF may work through effects on dendritic cells (DCs).
  
  
  METHODS
  Acute colitis was induced in Balb/c mice by administration of DSS in drinking water. Mice were treated with daily GM-CSF or phosphate-buffered saline (PBS). To probe the role of plasmacytoid DCs (pDCs) in the response to GM-CSF, we further examined the effects of monoclonal antibody 440c, which is specific for a sialic acid-binding immunoglobulin (Ig)-like lectin expressed on pDCs.
  
  
  RESULTS
  GM-CSF ameliorates acute DSS-induced colitis, resulting in significantly improved clinical parameters and histology. Microarray analysis showed reduced expression of proinflammatory genes including TNF-alpha and IL1-beta; the results were further confirmed by real-time reverse-transcriptase polymerase chain reaction and serum Bio-plex analysis. GM-CSF treatment significantly expands pDCs and type 1 IFN production. Administration of mAb 440c completely blocked the therapeutic effect of GM-CSF. GM-CSF is also effective in RAG1(-/-) mice, demonstrating activity-independent effects on T and B cells. IFN-beta administration mimics the therapeutic effect of GM-CSF in DSS-treated mice. GM-CSF increases systemic and mucosal type 1 IFN expression and exhibits synergy with pDC activators, such as microbial cytosine-phosphate-guanosine (CpG) DNA.
  
  
  CONCLUSIONS
  GM-CSF is effective in the treatment of DSS colitis in a mechanism involving the 440c(+) pDC population.
authors.affiliation: Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Satheesh K
authors.initials: SK
authors.lastname: Sainathan
authors.forename: Eyad M
authors.initials: EM
authors.lastname: Hanna
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Gong
authors.forename: Kumar S
authors.initials: KS
authors.lastname: Bishnupuri
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Luo
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Frances V
authors.initials: FV
authors.lastname: White
authors.forename: Ed
authors.initials: E
authors.lastname: Croze
authors.forename: Courtney
authors.initials: C
authors.lastname: Houchen
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Brian K
authors.initials: BK
authors.lastname: Dieckgraefe
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007370:Interferon Type I / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D007370:Interferon Type I; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016264:Dextran Sulfate