Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 273, Issue 2, Pages 485-491Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/bbrc.2000.2969
Keywords
peroxisome proliferator-activated receptor gamma; vascular endothelial growth factor; prostaglandin; macrophage; colon carcinogenesis
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We previously reported that cyclooxygenase (COX)-2 was predominantly expressed in macrophages of human colonic adenomas (Int. J. Cancer 83, 470-475.). The role of prostaglandins (PGs) produced by COX-2-expressing macrophages in colon carcinogenesis is still unclear. Here we show that PGs up-regulate vascular endothelial growth factor (VEGF) production by activated macrophages through their specific receptors. mRNAs of both PGE-specific receptors and peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, were expressed in phorbol 12-myristate 13-acetate-differentiated U937, a human macrophage model (H-Mac), Prostaglandin E-1 (PGE(1)) and 15-deoxy-Delta(12,14)-PGJ(2) (a potent PPAR gamma ligand, 15d-PGJ(2)) dramatically increased VEGF production. The combination of PGE(1) and 15d-PGJ(2) additively increased VEGF production. In addition, PGE(1) significantly increased cAMP formation, whereas 15-dPGJ(2) did not affect cAMP formation. The effect of the combination of PGE(1) and 15d-PGJ(2) on cAMP formation was similar to that of PGE(1) alone. Unexpectedly, 15d-PGJ(2) also drastically increased IL-1 beta production, an indicator of macrophage activation, although PGE(1) only mildly increased it. Additional enhancement of IL-1 beta production was observed in the combination of PGE(1) and 15d-PGJ(2). These results suggest that PGs dramatically increased VEGF production by activated macrophages through specific PGE receptor and PPAR gamma-mediated processes and that PGs may thereby promote tumor growth through VEGF production. (C) 2000 Academic Press.
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