Journal article
Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis
Inflammatory bowel diseases, Vol.14(1), pp.88-99
01/01/2008
DOI: 10.1002/ibd.20279
PMCID: PMC4565141
PMID: 17932977
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. GMCSF 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.
Details
- Title: Subtitle
- Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis
- Creators
- Satheesh K. Sainathan - Washington University in St. LouisEyad M. Hanna - Washington University in St. LouisQingqing Gong - Washington University in St. LouisKumar S. Bishnupuri - Washington University in St. LouisQizhi Luo - Washington University in St. LouisMarco Colonna - Washington University in St. LouisFrances V. White - Washington University in St. LouisEd Croze - University of Oklahoma Health Sciences CenterCourtney Houchen - University of Oklahoma Health Sciences CenterShrikant Anant - University of Oklahoma Health Sciences CenterBrian K. Dieckgraefe - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- Inflammatory bowel diseases, Vol.14(1), pp.88-99
- DOI
- 10.1002/ibd.20279
- PMID
- 17932977
- PMCID
- PMC4565141
- NLM abbreviation
- Inflamm Bowel Dis
- ISSN
- 1078-0998
- eISSN
- 1536-4844
- Publisher
- Oxford Univ Press
- Number of pages
- 12
- Grant note
- I01BX003072 / Veterans Affairs; US Department of Veterans Affairs Z01 DK060106 / Intramural NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 AI069390; AI 069390 / NIAID NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T 32 HD007507-09 / NICHD NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) P30DK052574 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) I01 BX003072 / BLRD VA T32HD007507 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R01AI069390 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30 DK052574; P30 DK52574; R01 DK060106; R56 DK060106 / NIDDK NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 01/01/2008
- Academic Unit
- Stead Family Department of Pediatrics; Gastroenterology, Hepatology, Pancreatology, and Nutrition
- Record Identifier
- 9984354052602771
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