The cellular and molecular origin of tumor-associated macrophages.

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an "alternatively activated" phenotype.

Tgf-β1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development.

TGFβ1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors. Our recent study revealed that T cell-produced TGFβ1 is essential for inhibiting cytotoxic T cell responses to tumors. However, the exact TGFβ1-producing T cell subset required for tumor immune evasion remains unknown.

T cell- but not tumor cell-produced TGF-β1 promotes the development of spontaneous mammary cancer.

During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-β1. We showed in our recent studies that T cell-produced TGF-β1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-β1 produced by tumor cells in tumor development.

T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine.

Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the cellular mechanism by which TGF-β induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T cells from the tumor-draining lymph nodes.

Alpha-melanocyte-stimulating hormone down-regulates CXC receptors through activation of neutrophil elastase.

Considering the role of interleukin-8 (IL-8) in a large number of acute and chronic inflammatory diseases, the regulation of IL-8-mediated biological responses is important. Alpha-melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide, inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that alpha-MSH interacts predominantly with melanocortin-1 receptors and inhibits several IL-8-induced biological responses in macrophages and neutrophils.

Cardiac glycoside inhibits IL-8-induced biological responses by downregulating IL-8 receptors through altering membrane fluidity.

Considering the potential role of interleukin-8 (IL-8) in inflammation, angiogenesis, tumorogenesis, and metastasis, and the involvement of different cell types especially neutrophils and macrophages in those processes, the regulation of IL-8-mediated biological responses is important. In this report we provide evidences that oleandrin, a cardiac glycoside potentially inhibited IL-8-, formyl peptide (FMLP)-, EGF-, or nerve growth factor (NGF)-, but not IL-1- or TNF-induced NF-kappaB activation in macrophages. Oleandrin inhibited IL-8-, but not TNF-induced NF-kappaB-dependent genes expression.

beta-D-Glucoside suppresses tumor necrosis factor-induced activation of nuclear transcription factor kappaB but potentiates apoptosis.

Mangiferin, a natural polyphenol is known to exhibit anti-inflammatory, antioxidant, and antiviral effects. However the molecular mechanism underlying these effects has not been well characterized. Because NF-kappaB plays an important role in these processes, it is possible that mangiferin modulates NF-kappaB activation.

Oleandrin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 and potentiates apoptosis induced by ceramide.

Ceramide (N-acetyl-D-sphingosine), a second messenger for cell signaling induces transcription factors, like nuclear factor-kappa B (NF-kappa B), and activator protein-1 (AP-1) and is involved in inflammation and apoptosis. Agents that can suppress these transcription factors may be able to block tumorigenesis and inflammation. Oleandrin (trans-3,4',5-trihydroxystilbene), a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, has been used in the treatment of cardiac abnormalities in Russia and China for years.

alpha-Melanocyte-stimulating hormone inhibits lipopolysaccharide-induced biological responses by downregulating CD14 from macrophages.

Monocytes/macrophages are the first cells involved in inflammation. alpha-Melanocyte-stimulating hormone (alpha-MSH) is known to possess an anti-inflammatory role induced by a variety of stimuli; however, the molecular mechanisms underlying these effects are not clearly defined. In this report we provide evidence that alpha-MSH inhibited serum-activated lipopolysaccharide (SA-LPS)-induced proteolytic enzyme release, oxidative burst response, reactive oxygen intermediate generation, nitric oxide production, and adhesion molecule expression in monocyte-derived macrophages.

alpha-Melanocyte-stimulating hormone induces cell death in mast cells: involvement of NF-kappaB.

Mast cells play a major role in the initiation of inflammation and allergic reactions. As cell numbers are tightly controlled by the interplay of factors affecting cell proliferation, development, and death the regulation of mast cell number may be important. Melanocyte-stimulating hormone inhibits most forms of inflammation by an unknown mechanism.

Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation.

Nuclear transcription factor kappa B (NF-kappaB) has been shown both to block apoptosis and to promote cell proliferation, and hence has been considered an important target for anticancer drug development. The pyrimidine analogue cytosine arabinoside (araC) is among the most effective agents used in the treatment of acute leukemia, and we demonstrate in this study that its chemotherapeutic activity may be mediated by its inhibition of NF-kappaB. We found that in Jurkat cells, although tumor necrosis factor (TNF), araC, or ceramide induced NF-kappaB, the induction was only transient in the case of araC.