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

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 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.

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

“…First, macrophages from c-fos knockout mice produced significantly more IL-12p70 as compared with macrophages from wild type mice (41). Second, transfection of RAW264.7 cells with a dominant-negative mutant of AP-1 dramatically enhanced IL-12p40 production (40). Our findings are further supported by a recent study showing that histamine enhances AP-1 DNA binding in keratinocytes (42).…”

“…Thus, we conclude that H4R signaling is able to induce the transcription factor AP-1 without phosphorylation of ERK1/2. AP-1, a heterodimer consisting of c-Fos and c-Jun, is a downstream target for MAPK pathways, i.e., ERK1/2, JNK, and p38 MAPK (40). AP-1 activation has been previously related to the inhibition of IL-12p70 in different studies.…”

Photodynamic therapy and anti-tumour immunity

“…Although PGE2 is proinflammatory, it is usually thought to have immunosuppressive effects 78 . PGE2 levels were attenuated in cells that were coincubated with the COX2 inhibitor NS-398.…”

Distinct Role of Macrophages in Different Tumor Microenvironments

“…For example, macrophage expression of IL-12, a cytokine known to stimulate both the proliferation and cytotoxicity of T cells and NK cells (60), is markedly suppressed in tumors, possibly by exposure to IL-10, PGE 2 , and TGF-h1 (8,61). By coinjecting mice with human prostate tumor cells and macrophages engineered to overexpress IL-12, Satoh et al (62) showed that it was possible to quickly reestablish enhanced expression of MHC in TAMs along with increased T-cell infiltration and an antitumor immune response, resulting in a marked reduction in the growth of both the primary tumor and lung metastases.…”