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

Third Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

Correspondence to:
Correspondence to:
Professor C Sakamoto
Third Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan; choitsu{at}nms.ac.jp

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)-1 and MIP-1ß, 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.

Abbreviations: 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

Keywords: cyclooxygenase; macrophage chemoattractant protein; adenoma; macrophage

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