Systemic administration of the chemokine macrophage inflammatory protein 1 exacerbates inflammatory bowel disease in a mouse model

Abstract

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 1α (MIP-1α) 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-1α. On day 7, mice were killed and pieces of colon taken for immunohistology and polymerase chain reaction analysis. The direct effects of MIP-1α on mucosal T cells and fibroblasts in vitro were also investigated. Results: Systemic administration of MIP-1α 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 γ (IFN-γ) levels, and increased transcripts for tumour necrosis factor α (TNF-α) and matrix metalloproteinase 3 (MMP3). Isolated lamina propria lymphocytes from mice with TNBS colitis contained increased numbers of IFN-γ and TNF-α transcripts when stimulated with MIP-1α in vitro. Colonic lamina propria fibroblasts also responded to MIP-1α 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-1α, exacerbates immune mediated colitis. The effect seems to be due to the ability of MIP-1α to boost Th1 responses in the gut wall. Our findings also suggest a potential pathway by which peripheral infections can exacerbate inflammatory bowel disease.