Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice

Kuroda, Etsushi; Yamashita, Uki

doi:10.4049/jimmunol.170.2.757

Cited by 122 publications

(105 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Importantly, we found that Th2 cytokines IL-4, IL-10, and IL-13 could upregulate the expression of CD206 and legumain on the macrophage cell line RAW. This finding can best be understood when one considers that macrophages are derived from peripheral blood and differentiate into M2 macrophages once they are recruited into tumor sites where IL-4, IL-13, and IL-10 are released by tumor cells and tumor stromal cells (3,19,29,31). Thus, targeting of M2 macrophages expressing legumain not only benefits suppression of tumor growth and metastases but also maintains the normal functions of macrophages with the M1 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Targeting tumor-associated macrophages as a novel strategy against breast cancer

Luo¹

2006

Journal of Clinical Investigation

499

401

View full text Add to dashboard Cite

Tumor-associated macrophages (TAMs) are associated with tumor progression and metastasis. Here, we demonstrate for the first time that legumain, a member of the asparaginyl endopeptidase family functioning as a stress protein, overexpressed by TAMs, provides an ideal target molecule. In fact, a legumain-based DNA vaccine served as a tool to prove this point, as it induced a robust CD8 + T cell response against TAMs, which dramatically reduced their density in tumor tissues and resulted in a marked decrease in proangiogenic factors released by TAMs such as TGF-b, TNF-a, MMP-9, and VEGF. This, in turn, led to a suppression of both tumor angiogenesis and tumor growth and metastasis. Importantly, the success of this strategy was demonstrated in murine models of metastatic breast, colon, and non-small cell lung cancers, where 75% of vaccinated mice survived lethal tumor cell challenges and 62% were completely free of metastases. In conclusion, decreasing the number of TAMs in the tumor stroma effectively altered the tumor microenvironment involved in tumor angiogenesis and progression to markedly suppress tumor growth and metastasis. Gaining better insights into the mechanisms required for an effective intervention in tumor growth and metastasis may ultimately lead to new therapeutic targets and better anticancer strategies. IntroductionA novel antitumor strategy is immunization against molecules overexpressed by tumor-associated macrophages (TAMs) and thereby remodel the tumor microenvironment that attracts these macrophages and mediates their function (1, 2). TAMs consist primarily of a polarized M2 (F4/80 + /CD206 + ) macrophage population with little cytotoxicity for tumor cells because of their limited production of NO and proinflammatory cytokines (3). TAMs also possess poor antigen-presenting capability and effectively suppress T cell activation. In fact, these macrophages of M2 phenotype actually promote tumor cell proliferation and metastasis by secreting a wide range of growth and proangiogenic factors as well as metalloproteinases and by their involvement in signaling circuits that regulate the function of fibroblasts in the tumor stroma (4). In recent studies, anti-TAM effects induced by small molecule inhibitors contributed to tumor suppression (5, 6). For example, the antineoplastic agent Yondelis has a selective cytotoxic effect on TAMs, thereby significantly reducing their production of IL-6 and CCL2, which, in turn, contribute to growth suppression of inflammation-associated human tumors (7). Another such example is provided by a biphosphonate compound, zoledronic acid, that suppresses MMP-9 secretion by TAMs, thereby inhibiting tumor metalloproteinase activity and diminishing the association of VEGF with its tyrosine kinase receptors on proliferating endothelial cells (8). In a different experimental model, the chemokine CCL5 was shown to be key in the recruitment of TAMs, and an antagonist of this chemokine reduced the tumor infiltrate and slowed tumor growth (9). Hence, although the therapeutic ta...

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting tumor-associated macrophages as a novel strategy against breast cancer

Luo¹

2006

Journal of Clinical Investigation

499

401

View full text Add to dashboard Cite

show abstract

“…Considering that prostaglandins are involved in the paracrine regulation of the rupture of ovarian follicles associated with ovulation (Priddy & Killick 1993) and that PGE has been reported to have immunomodulatory properties by modulating cytokine production (Kuroda & Yamashita 2003, Lakier Smith 2003, Yang et al 2003, we also evaluated whether the ovarian concentration of PGE was modified by DHEA-induced hyperandrogenization. The fact that the treatment with DHEA reduced ovarian PGE production was an expected result since DHEAhyperandrogenized animals not only did not start to cycle but also showed increased levels of TNF-a when compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Role of the N, N′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

Sander¹,

Luchetti²,

Solano³

et al. 2006

Reproduction

View full text Add to dashboard Cite

The present study investigated the role of the N, N{ 0 }-dimethylbiguanide metformin (50 mg/100 g body weight in 0.05 ml water, given orally with a canulla) in the prevention of endocrine and immune disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The treatment with DHEA (6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days, recreates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA did not modify either body mass index (BMI) or blood glucose levels, but did increase fasting insulin levels when compared with controls. Markers of ovarian function -serum estradiol (E), progesterone (P) and ovarian prostaglandin E (PGE) -were evaluated. The treatment with DHEA increased serum E and P levels while ovarian PGE diminished. When metformin was administered together with DHEA, serum insulin, E and P levels, and ovarian PGE values did not differ when compared with controls. Using flow cytometry assays we found that the treatment with DHEA diminished the percentage of the CD4 1 T lymphocyte population and increased the percentage of the CD8 1 T lymphocyte population from both ovarian tissue and retroperitoneal lymph nodes. However, when metformin was administered together with DHEA, the percentages of CD4 1 and CD8 1 T lymphocyte populations from both ovarian tissue and retroperitoneal lymph nodes were similar to those observed in controls. Finally, when DHEA was administered alone it increased the serum tumor necrosis factor-alpha (TNF-a) levels when compared with controls; however, when metformin was administered together with DHEA, serum TNF-a levels were similar to controls. These results indicate that metformin is able, directly or indirectly, to avoid the endocrine and immune alterations produced when mice are hyperandrogenized with DHEA.

show abstract

“…PGE 2 induced in response to LPS plus IFN-␥ can also contribute to the attenuation of transcriptional response at 4 h. Exogenously added PGE 2 inhibits LPS-induced gene expression and production of cytokines, including TNF-␣ (18, 58 -60). PGE 2 is also induced after 2-4 h of LPS stimulation in macrophages (61)(62)(63)(64)(65)(66), and endogenous PGE 2 can reach a level that is effective in inhibiting TNF-␣ production (21,67). However, a recent report suggested that in RAW 264.7 cells, PGs induced by LPS is incapable of inhibiting TNF-␣ production, as treatment with COX inhibitors did not alter TNF-␣ gene expression and production (68).…”

Section: Lps Plus Ifn-␥: the Attenuation Of Lps-induced Late Transcrimentioning

confidence: 99%

Dual Ligand Stimulation of RAW 264.7 Cells Uncovers Feedback Mechanisms That Regulate TLR-Mediated Gene Expression

Zhu

Chang

Hsueh

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

To characterize how signaling by TLR ligands can be modulated by non-TLR ligands, murine RAW 264.7 cells were treated with LPS, IFN-γ, 2-methyl-thio-ATP (2MA), PGE2, and isoproterenol (ISO). Ligands were applied individually and in combination with LPS, for 1, 2, and 4 h, and transcriptional changes were measured using customized oligo arrays. We used nonadditive transcriptional responses to dual ligands (responses that were reproducibly greater or less than the expected additive responses) as a measure of pathway interaction. Our analysis suggests that cross-talk is limited; <24% of the features with significant responses to the single ligands responded nonadditively to a dual ligand pair. PGE2 and ISO mainly attenuated, while 2MA enhanced, LPS-induced transcriptional changes. IFN-γ and LPS cross-regulated the transcriptional response induced by each other: while LPS preferentially enhanced IFN-γ-induced changes in gene expression at 1 h, IFN-γ signaling primarily attenuated LPS-induced changes at 4 h. Our data suggest specific cross-talk mechanisms: 1) LPS enhances the expression of IFN-γ- response genes by augmenting STAT1 activity and by activating NF-κB, which synergizes with IFN-γ-induced transcriptional factors; 2) IFN-γ attenuates the late LPS transcriptional response by increasing the expression of suppressor of cytokine signaling 1 and cytokine-inducible SH2-containing protein expression; 3) 2MA modulates LPS secondary transcriptional response by increasing IFN-β and inhibiting IL-10 gene expression; 4) PGE2 and ISO similarly regulate the LPS transcriptional response. They increase IL-10 transcription, resulting in attenuated expression of known IL-10-suppressed genes.

show abstract

Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice

Cited by 122 publications

References 59 publications

Targeting tumor-associated macrophages as a novel strategy against breast cancer

Targeting tumor-associated macrophages as a novel strategy against breast cancer

Role of the N, N′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

Dual Ligand Stimulation of RAW 264.7 Cells Uncovers Feedback Mechanisms That Regulate TLR-Mediated Gene Expression

Contact Info

Product

Resources

About