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Regulation of interleukin‐12 gene expression and its anti‐tumor activities by prostaglandin E 2 derived from mammary carcinomas
Author(s) -
Mitsuhashi Maki,
Liu Jianguo,
Cao Shanjin,
Shi Xiaoyan,
Ma Xiaojing
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1203641
Subject(s) - biology , immune system , prostaglandin e2 , cancer research , endogeny , cytokine , in vivo , prostaglandin e , metastasis , immunology , endocrinology , cancer , genetics , microbiology and biotechnology
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 E 2 (PGE 2 ) 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, PGE 2 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 PGE 2 synthesis. Moreover, PGE 2 ‐mediated inhibition of IL‐12 production requires the functional cooperation of AP‐1 and AP‐1 strongly suppresses IL‐12 p40 transcription. Blocking PGE 2 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‐γ. This study contributes to the elucidation of the molecular mechanisms underlying the interaction between a progressive malignancy and the immune defense apparatus.