Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma

Gut. 2006 Jan;55(1):54-61. doi: 10.1136/gut.2004.059824. Epub 2005 Aug 5.

Abstract

Background and aims: Cyclooxygenase 2 (COX-2) expression in subepithelial macrophages of colorectal adenoma has been suggested as the first in a series of steps leading to colorectal tumorigenesis. We tested the hypothesis that chemokines released from human colorectal adenoma epithelium might be involved in COX-2 expression in macrophages of the lamina propria.

Methods: Endoscopic samples of sporadic colorectal adenomas were tested by enzyme linked immunosorbent assay for chemokines involved in macrophage chemotaxis. Localisation of adenoma macrophage chemoattractant protein 1 (MCP-1) and COX-2 were determined by immunohistochemistry. The effects of MCP-1, in the presence or absence of celecoxib, on COX-2 expression, and prostaglandin (PG) E(2) and vascular endothelial growth factor (VEGF) release, were examined in human macrophages isolated from peripheral blood.

Results: MCP-1 levels were markedly higher in adenoma with mild-moderate dysplasia (129.7 (19.9) pg/mg protein) and severe dysplasia (227.9 (35.4) pg/mg protein) than in normal colonic mucosa (55.8 (4.2) pg/mg protein). Other chemokine levels, macrophage inflammatory proteins (MIP)-1alpha and MIP-1beta, and the chemokine regulated on activation of normal T cell expressed and secreted (RANTES) did not vary significantly between adenoma and normal mucosa. MCP-1 levels in both adenoma and normal colonic mucosa increased significantly three hours after tissue cultivation in vitro. MCP-1 immunoreactivity was restricted to the adenoma epithelium, with no reactivity seen in adjacent normal epithelial cells. MCP-1 stimulated COX-2 expression and PGE(2) and VEGF release in human macrophages. Celecoxib, a selective COX-2 inhibitor, inhibited MCP-1-induced PGE(2) and VEGF release in macrophages. Addition of exogenous PGE(2) reversed this inhibitory effect on VEGF release, suggesting that MCP-1 in adenoma epithelial cells might be involved in COX-2 expression and subsequent macrophage activation.

Conclusions: MCP-1 in colorectal adenoma epithelial cells might be involved in macrophage migration and COX-2 expression, leading to the subsequent development of colonic adenoma.

MeSH terms

  • Adenoma / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / analysis
  • Antigens, Differentiation, Myelomonocytic / analysis
  • Celecoxib
  • Cells, Cultured
  • Chemokine CCL2 / antagonists & inhibitors
  • Chemokine CCL2 / metabolism*
  • Chemokine CCL2 / pharmacology
  • Chemokines / metabolism
  • Colorectal Neoplasms / metabolism*
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / metabolism
  • Dinoprostone / pharmacology
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Humans
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Male
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Pyrazoles / pharmacology
  • Sulfonamides / pharmacology
  • Tissue Culture Techniques
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Chemokine CCL2
  • Chemokines
  • Cyclooxygenase Inhibitors
  • Neoplasm Proteins
  • Pyrazoles
  • Sulfonamides
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone