Published online before print May 3, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1203641

Received for publication December 18, 2003.
Revised March 22, 2004.
Accepted for publication April 13, 2004.

Article

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

Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York

^@ To whom correspondence should be addressed. E-mail: xim2002{at}med.cornell.edu.

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. Exposure of activated macrophages to PGE₂ enhances the activity of activated protein-1 (AP-1), a transcription factor that strongly suppresses IL-12 p40 transcription. Moreover, PGE₂-mediated inhibition of IL-12 production requires the functional cooperation of AP-1. 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-. This study contributes to the elucidation of the molecular mechanisms underlying the interaction between a progressive malignancy and the immune defense apparatus.

Key Words: activated protein-1 • cytotoxic T lymphocyte • natural killer cells

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