Induction of macrophagic prostaglandin E2 synthesis by glioma cells

Yoshiteru Nakano M.D. 1 , Etsushi Kuroda Ph.D. 1 , Tomohiro Kito M.D., Ph.D. 1 , Akira Yokota M.D., Ph.D. 1 and Uki Yamashita M.D., Ph.D. 1
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  • 1 Departments of Neurosurgery and Immunology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu; and Department of Neurosurgery, Niigata Rosai Hospital, Jyoetsu, Japan
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Object

It has been reported that glioma cells produce prostaglandin (PG)E2, which promotes the growth of tumor cells and possesses immunosuppressive activity, and that cyclooxygenase (COX) inhibitors impede tumor growth and infiltration. Macrophages in tumor-bearing hosts are activated to produce PGE2, which induces an immunosuppressive state. Note, however, that the precise mechanism by which PGE2 induces an immunosuppressive state is still unclear. In this study, the authors investigated the mechanism of PGE2 production in glioma-bearing hosts.

Methods

The human and murine glioma cells that were studied did not produce a significant amount of PGE2. However, the coculture of human peripheral blood mononuclear cells or murine peritoneal macrophages with glioma cells or conditioned glioma medium led to the production of a large amount of PGE2. In contrast, production of tumor necrosis factor and interleukin (IL)-12p70 by macrophages and cytotoxic T lymphocyte induction were suppressed by culturing with conditioned glioma medium; this suppression was abrogated by the addition of the COX inhibitor indomethacin. The macrophagic expression of COX-2, and particularly the expression of microsomal PGE synthase (mPGES)–1, a terminal enzyme of the arachidonate cascade, was enhanced by the glioma-derived soluble factors. Furthermore, IL-12p70 production was not clearly suppressed in macrophages from mPGES-1–deficient mice. The glioma-derived soluble factors were sensitive to treatment with heat and papain.

Conclusions

These results indicated that PGE2 production by macrophages is enhanced by glioma-derived soluble factors, which induce an immunosuppressive state in glioma-bearing hosts. Therefore, the inhibition of PGE2 synthesis, targeting COX-2 and mPGES-1, is an effective treatment for the induction of antiglioma immune responses.

Abbreviations used in this paper: COX = cyclooxygenase; cPGES = cytosolic prostaglandin E synthase; cPLA2 = cytosolic phospholipase A2; EIA = enzyme immunoassay; ELISA = enzymelinked immunosorbent assay; FCS = fetal calf serum; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; IL = interleukin; LPS = lipopolysaccharide; mAb = monoclonal antibody; mPGES = microsomal PGES; mRNA = messenger RNA; PBMC = peripheral blood mononuclear cell; PCR = polymerase chain reaction; PG = prostaglandin; RSV-M = Rous sarcoma virus-mouse; SDS-PAGE = sodium dodecyl sulfate-polyacrylamide gel electrophoresis; sPLA2 = secretory PLA2; TGF = transforming growth factor; TNF = tumor necrosis factor; TNP = trinitrophenyl.

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Contributor Notes

Address reprint requests to: Uki Yamashita, M.D., Ph.D., Department of Immunology, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan. email: yama-uki@med.uoeh-u.ac.jp.
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