The Correlation Between Proinflammatory Cytokines, MAdCAM-1 and Cellular Infiltration in the Inflamed Colon From TNF-alpha Gene Knockout Mice

Immunol Cell Biol. Nov-Dec 2007;85(8):633-9. doi: 10.1038/sj.icb.7100112. Epub 2007 Sep 4.

Abstract

Tumour necrosis factor (TNF) is important in the development of inflammatory bowel disease. TNF-alpha-deficient mice show more severe colonic inflammation than wild-type (Wt) mice, but the underlying mechanism remains unclear. Using immunohistochemistry, enzyme-linked-immunosorbent assay and histopathology, we found that there was a higher level of macrophage infiltration in TNF-alpha(-/-) compared to Wt mice. This is consistent with higher levels of monocyte chemotactic protein-1, interleukin (IL)-6 and granulocyte monocyte colony-stimulating factor (GM-CSF) in the inflamed colon from the TNF-alpha(-/-) mice, compared to the Wt mice, following dextran sulphate sodium (DSS) challenge. There was close correlation between clinical observations and histopathological findings in both Wt and TNF-alpha(-/-) mice. The expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was upregulated in the colon of Wt and TNF-alpha(-/-) mice following DSS challenge. Interestingly, the induction of MAdCAM-1 was relatively lower in the inflamed colon of TNF-alpha(-/-) mice, despite the higher inflammatory cell infiltrate, compared to their Wt counterparts. On the other hand, TNF-alpha(-/-) mice had significantly lower baseline levels of colonic IL-4, IL-6 and GM-CSF. Furthermore, there was a reduction of both immunoglobulin A (IgA) and IgG in the gut from TNF-alpha(-/-) mice following DSS challenge. These data indicate that TNF-alpha deficiency alters homoeostasis of the colonic chemokine/cytokine environment and humoral immune response, resulting in an exacerbation of acute DSS-induced colitis in TNF-alpha(-/-) mice. These findings support the idea that TNF-alpha plays a role in the acute stage of intestinal inflammation.

MeSH terms

  • Animals
  • Cell Adhesion Molecules / immunology*
  • Cell Movement*
  • Colitis / chemically induced
  • Colitis / immunology*
  • Cytokines / immunology*
  • Dextran Sulfate
  • Disease Susceptibility
  • Immunoglobulin A / immunology
  • Immunoglobulin G / immunology
  • Inflammation Mediators / immunology*
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / immunology
  • Tumor Necrosis Factor-alpha / deficiency*
  • Weight Loss

Substances

  • Cell Adhesion Molecules
  • Cytokines
  • Immunoglobulin A
  • Immunoglobulin G
  • Inflammation Mediators
  • Madcam1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate