The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T3), in triggering the differentiation of bone marrow-derived monocytes into unpolarized macrophages. T3-induced macrophages displayed a classically activated (M1) signature. A T3-induced M1-priming effect was also observed on polarized macrophages because T3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo, circulating T3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T3 levels increased the recruited (potentially damaging) cells, whereas restoring T3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor β1 as the major player mediating T3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems.
Melanoma is a rapidly growing and highly metastatic cancer with high mortality rates, for which a resolutive treatment is lacking. Identification of novel therapeutic strategies and biomarkers of tumour stage is thus of particular relevance. We report here on a novel biomarker and possible candidate therapeutic target, the sphingolipid metabolising enzyme acid sphingomyelinase (A-SMase). A-SMase expression correlates inversely with tumour stage in human melanoma biopsies. Studies in a mouse model of melanoma and on cell lines derived from mouse and human melanomas demonstrated that A-SMase levels of expression actually determine the malignant phenotype of melanoma cells in terms of pigmentation, tumour progression, invasiveness and metastatic ability. The action of A-SMase is mediated by the activation of the extracellular signal-regulated kinase, the subsequent proteasomal degradation of the Microphtalmia-associated transcription factor (Mitf) and inhibition of cyclin-dependent kinase 2, Bcl-2 and c-Met, downstream targets of Mitf involved in tumour cell proliferation, survival and metastatisation.
Acid sphingomyelinase (A-SMase) is an important enzyme in sphingolipid metabolism and plays key roles in apoptosis, immunity, development, and cancer. In addition, it mediates cytotoxicity of cisplatin and some other chemotherapeutic drugs. The mechanism of A-SMase activation is still undefined. We now demonstrate that, upon CD95 stimulation, ASMase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4. Indeed, downregulation of syntaxin 4 inhibits A-SMase translocation and activation induced by CD95 stimulation. This leads to inhibition of the CD95-triggered signaling events, including caspase 3 and 9 activation and apoptosis, activation of the survival pathway involving the protein kinase Akt, and important changes in cell cycle and proliferation. The molecular interaction between A-SMase and syntaxin 4 was not known and clarifies the mechanism of A-SMase activation. The novel actions of syntaxin 4 in sphingolipid metabolism and exocytosis we describe here define signaling mechanisms of broad relevance in cell pathophysiology.Acid sphingomyelinase (A-SMase) 3 (EC 3.1.4.12) is a phosphodiesterase that catalyzes the hydrolysis of membrane lipid sphingomyelin to ceramide and phosphorylcholine. The enzyme plays important roles in pathophysiology, as it mediates the action of several apoptogenic molecules, cytokines, and neurotrophins, regulating neuronal function, immunity, and infections (1-3).Enzymatic dysfunction of A-SMase leads to Niemann-Pick diseases types A and B (4). The enzyme is also important in cancer development and therapy; tumor growth is enhanced in A-SMase knock-out mice (5), and the enzyme contributes significantly to the cytotoxic effects of several anticancer drugs (6 -9). The biology of A-SMase under resting conditions, including its localization to lysosomal compartments, has been clarified (6, 9). Less clear is how A-SMase is activated. Activation has been suggested to require translocation from intracellular compartments to the extracellular surface of the cell through pathways as yet unknown (3, 9) or to occur within the lysosomes (10). Elucidating the molecular mechanisms of A-SMase activation is of biological relevance and might reveal novel candidate targets for therapy, including cancer therapy.Using U373, a human glioma cell line expressing the death receptor CD95, we have now established that translocation of A-SMase to the plasma membrane is required for its early activation, that this process takes place by exocytosis, and that a key role in it is played by syntaxin 4, an ubiquitously expressed t-SNARE implicated in several regulated exocytic pathways including the translocation of Glut4 to the plasma membrane, exocytosis of secretory granules, and the calcium-dependent release of lysosomes (11,12). Furthermore, we demonstrate that the blockade of syntaxin 4-dependent exocytosis inhibits CD95 receptor clustering and internalization, caspase activation and loss of mitochondrial membr...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.