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

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)-1a and MIP-1b, 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.

Inhibition of Monocyte Chemoattractant Protein-1 Ameliorates Rat Adjuvant-Induced Arthritis

“…First, in arthritic joints, VEGF is produced by synovial macrophages and fibroblasts (46,47), and VEGF levels may decrease due to reduced monocyte recruitment. Second, MCP-1 induces VEGF production in human macrophages and aortic endothelial cells (48,49), and therefore, inhibition of MCP-1 function may reduce VEGF produced by ST macrophages. Third, TNF-␣ increases VEGF secretion (50), and decreased levels of TNF-␣ may explain the reduced levels of joint VEGF.…”

Blockade of a Chemokine, CCL2, Reduces Chronic Colitis-Associated Carcinogenesis in Mice

“…COX-2 protein was detected in infiltrating F4/80-positive cells (10) and CCR2-expressing cells. Moreover, CCL2 can induce COX-2 expression in human monocytes (50). Thus, CCL2 blocking may reduce the infiltration of COX-2-expressing F4/80-positive cells and depress COX-2 expression by infiltrating macrophages, and eventually inhibit the Wnt signaling pathway and neovascularization, resulting in retardation of cancer progression.…”

Control of murine Ly6Chigh monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6

“…CCL2 was previously reported to sustain an autocrine pathway leading to COX2 upregulation in human monocytes. 35 Similarly, in BM-derived macrophages (BMDM) from WT but not CCR2 Ϫ/Ϫ mice, CCL2 upregulated COX2 and ARG1 expression levels ( Figure 5G). These data indicate that delayed inflammatory chemokine clearance in the absence of D6 not only induces accumulation of immature Ly6C high monocytes in blood and secondary lymphoid organs but also increases their suppressive capacity by inducing COX2 and ARG1 expression.…”