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Regulation of interleukin-12 gene expression and its anti-tumor activities by prostaglandin E2 derived from mammary carcinomas.

TitleRegulation of interleukin-12 gene expression and its anti-tumor activities by prostaglandin E2 derived from mammary carcinomas.
Publication TypeJournal Article
Year of Publication2004
AuthorsMitsuhashi M, Liu J, Cao S, Shi X, Ma X
JournalJ Leukoc Biol
Volume76
Issue2
Pagination322-32
Date Published2004 Aug
ISSN0741-5400
KeywordsAnimals, Antineoplastic Agents, Cyclooxygenase 2, Dinoprostone, Female, Gene Expression Regulation, Neoplastic, Interleukin-12, Isoenzymes, Macrophages, Mammary Neoplasms, Animal, Mice, Prostaglandin-Endoperoxide Synthases, RNA, Messenger
Abstract

Interleukin-12 (IL-12)-mediated immune responses are critical for the control of malignant development. Tumors can actively resist detrimental immunity of the host via many routes. Prostaglandin E2 (PGE2) is one of the major immune-suppressive factors derived from many types of tumors. Here, we show that systemic administration of recombinant IL-12 could therapeutically control the growth of aggressive TS/A and 4T1 mouse mammary carcinomas. However, PGE2 produced by tumors potently inhibits the production of endogenous IL-12 at the level of protein secretion, mRNA synthesis, and transcription of the constituent p40 and p35 genes. The inhibition can be reversed by NS-398, a selective inhibitor of the enzymatic activity of cyclooxygenase 2 in PGE2 synthesis. Moreover, PGE2-mediated inhibition of IL-12 production requires the functional cooperation of AP-1 and AP-1 strongly suppresses IL-12 p40 transcription. Blocking PGE2 production in vivo results in a marked reduction in lung metastasis of 4T1 tumors, accompanied by enhanced ability of peritoneal macrophages to produce IL-12 and spleen lymphocytes to produce interferon-gamma. This study contributes to the elucidation of the molecular mechanisms underlying the interaction between a progressive malignancy and the immune defense apparatus.

DOI10.1189/jlb.1203641
Alternate JournalJ Leukoc Biol
PubMed ID15123779
PubMed Central IDPMC2965202
Grant ListR01 AI045899 / AI / NIAID NIH HHS / United States
R01 CA100223 / CA / NCI NIH HHS / United States
R01 CA100223-01A1 / CA / NCI NIH HHS / United States
AI45899 / AI / NIAID NIH HHS / United States

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