Prostaglandins up-regulate vascular endothelial growth factor production through distinct pathways in differentiated U937 cells.
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 (PPARgamma), 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 PPARgamma 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 15d-PGJ(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-1beta production, an indicator of macrophage activation, although PGE(1) only mildly increased it. Additional enhancement of IL-1beta 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 PPARgamma-mediated processes and that PGs may thereby promote tumor growth through VEGF production.
Bamba
H
H
First Department of Internal Medicine, Saitama Medical Center, Saitama, 350-8550, Japan. bam@saitama-med.ac.jp
Ota
S
S
Kato
A
A
Kawamoto
C
C
Fujiwara
K
K
D000527:Alprostadil / Q000494:pharmacology*; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000209:etiology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000235:genetics; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis*; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017931:DNA Primers; D016228:Endothelial Growth Factors; D007375:Interleukin-1; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018078:Receptors, Prostaglandin E; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000527:Alprostadil; D015230:Prostaglandin D2