Article Text
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) E2 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)-1α and MIP-1β, 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 PGE2 and VEGF release in human macrophages. Celecoxib, a selective COX-2 inhibitor, inhibited MCP-1-induced PGE2 and VEGF release in macrophages. Addition of exogenous PGE2 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.
- COX-2, cyclooxygenase 2
- MCP-1, macrophage chemoattractant protein
- PG, prostaglandin
- VEGF, vascular endothelial growth factor
- RANTES, regulated on activation of normal T cell expressed and secreted
- ELISA, enzyme linked immunosorbent assay
- MIP, macrophage inflammatory protein
- NSAIDs, non-steroidal anti-inflammatory drugs
- FAP, familial adenomatous polyposis
- H&E, haematoxylin and eosin
- PBS, phosphate buffered saline
- EDTA, ethylenediaminetetraacetic acid
- PMSF, phenylmethylsulfonyl fluoride
- FITC, fluorescein isothiocyanate
- PBMC, peripheral blood mononuclear cells
- FCS, fetal calf serum
- LPS, lipopolysaccharide
- CHAPS, 3-[(3,cholamidopropyl)-dimethylammonio]-l-propane-sulfonate
- cyclooxygenase
- macrophage chemoattractant protein
- adenoma
- macrophage
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- COX-2, cyclooxygenase 2
- MCP-1, macrophage chemoattractant protein
- PG, prostaglandin
- VEGF, vascular endothelial growth factor
- RANTES, regulated on activation of normal T cell expressed and secreted
- ELISA, enzyme linked immunosorbent assay
- MIP, macrophage inflammatory protein
- NSAIDs, non-steroidal anti-inflammatory drugs
- FAP, familial adenomatous polyposis
- H&E, haematoxylin and eosin
- PBS, phosphate buffered saline
- EDTA, ethylenediaminetetraacetic acid
- PMSF, phenylmethylsulfonyl fluoride
- FITC, fluorescein isothiocyanate
- PBMC, peripheral blood mononuclear cells
- FCS, fetal calf serum
- LPS, lipopolysaccharide
- CHAPS, 3-[(3,cholamidopropyl)-dimethylammonio]-l-propane-sulfonate
Footnotes
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Conflict of interest: None declared.