Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis.
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.
Sainathan
Satheesh K
SK
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.
Hanna
Eyad M
EM
Gong
Qingqing
Q
Bishnupuri
Kumar S
KS
Luo
Qizhi
Q
Colonna
Marco
M
White
Frances V
FV
Croze
Ed
E
Houchen
Courtney
C
Anant
Shrikant
S
Dieckgraefe
Brian K
BK
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
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