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Published on: August 1, 2012
Systemic administration of the chemokine macrophage inflammatory protein 1alpha exacerbates inflammatory bowel
S L-F Pender1, V Chance, C V Whiting
1Division of Infection, Inflammation, and Repair, University of Southampton School of Medicine, UK
Introduction:
Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha) exacerbates colitis in a mouse model.
Methods:
Colitis was induced in Balb/c mice using trinitrobenzene sulfonic acid (TNBS). Starting four days later, animals received daily intraperitoneal injections of recombinant MIP-1alpha. On day 7, mice were killed and pieces of colon taken for immunohistology and polymerase chain reaction analysis. The direct effects of MIP-1alpha on mucosal T cells and fibroblasts in vitro were also investigated.
Results:
Systemic administration of MIP-1alpha markedly enhanced colitis with mice developing large transmural ulcers filled with granulation tissue. Treatment resulted in increased numbers of CD4 cells infiltrating the colonic lamina propria, increased interferon gamma (IFN-gamma) levels, and increased transcripts for tumour necrosis factor alpha (TNF-alpha) and matrix metalloproteinase 3 (MMP3). Isolated lamina propria lymphocytes from mice with TNBS colitis contained increased numbers of IFN-gamma and TNF-alpha transcripts when stimulated with MIP-1alpha in vitro. Colonic lamina propria fibroblasts also responded to MIP-1alpha with increased proliferation and decreased collagen 1 synthesis but fibroblast proliferation was not seen in vivo.
Conclusions:
These experiments show that increasing serum concentrations of a chemokine, MIP-1alpha, exacerbates immune mediated colitis. The effect seems to be due to the ability of MIP-1alpha to boost Th1 responses in the gut wall. Our findings also suggest a potential pathway by which peripheral infections can exacerbate inflammatory bowel disease.
Insights
Systemic administration of macrophage inflammatory protein 1-alpha (MIP-1alpha) worsens colitis in mice by boosting Th1 immune responses in the gut. This suggests a mechanism linking peripheral infections to inflammatory bowel disease exacerbations.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Inflammatory bowel disease (IBD) exacerbations are linked to infections.
- Infections elevate chemokine levels, prompting investigation into their role.
Purpose of the Study:
- To determine if systemic macrophage inflammatory protein 1-alpha (MIP-1alpha) administration exacerbates colitis in a mouse model.
- To elucidate the mechanisms by which MIP-1alpha affects the colonic immune environment.
Main Methods:
- Colitis induced using trinitrobenzene sulfonic acid (TNBS) in Balb/c mice.
- Daily intraperitoneal injections of recombinant MIP-1alpha administered.
- Colon tissue analyzed via immunohistology and PCR; in vitro studies on T cells and fibroblasts.
Main Results:
- MIP-1alpha administration significantly worsened colitis, causing transmural ulcers.
- Increased CD4 cell infiltration, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and matrix metalloproteinase 3 (MMP3) transcripts observed.
- In vitro, MIP-1alpha boosted IFN-gamma and TNF-alpha in lymphocytes and increased fibroblast proliferation.
Conclusions:
- Elevated serum MIP-1alpha exacerbates immune-mediated colitis.
- MIP-1alpha enhances Th1 responses in the gut wall.
- Findings suggest a pathway for peripheral infections exacerbating IBD.
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