Exogenous or endogenous Toll-like receptor ligands: which is the MVP in tumorigenesis?
ABSTRACT Toll-like receptors (TLRs) are a class of pattern recognition receptors sensing microbial components and triggering an immune response against pathogens. In addition to their role in anti-infection immunity, increasing evidence indicates that engagement of TLRs can promote cancer cell survival and proliferation, induce tumor immune evasion, and enhance tumor metastasis and chemoresistance. Recent studies have demonstrated that endogenous molecules or damage-associated molecular patterns released from damaged/necrotic tissues are capable of activating TLRs and that the endogenous ligands-mediated TLR signaling is implicated in the tumor development and affects the therapeutic efficacy of tumors. Since both exogenous and endogenous TLR ligands can initiate TLR signaling, which is the most valuable player in tumor development becomes an interesting question. Here, we summarize the effect of TLR signaling on the development and progression of tumors, and discuss the role of exogenous and endogenous TLR ligands in the tumorigenesis.
- SourceAvailable from: Henrique Borges da Silva[Show abstract] [Hide abstract]
ABSTRACT: Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88-/-) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88-/- animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88-/- mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning.Toxicon 03/2013; · 2.92 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) infection is associated with numerous liver diseases and causes serious global health problems, but the mechanisms underlying the pathogenesis of HCV infections remain largely unknown. In this study, we demonstrated that signal transducer and activators of transcription 3 (STAT3), matrix metalloproteinase-2 (MMP-2), and B-cell lymphoma 2 (Bcl-2) were significantly stimulated in HCV-infected patients. We further showed that HCV activates STAT3, MMP2, Bcl-2, extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) in infected Huh7.5.1 cells. Functional screening of HCV proteins revealed that the nonstructural protein 4B (NS4B) is reponsible for the activation of MMP-2 and Bcl-2 by stimulating STAT3 through repressing the suppressor of cytokine signaling 3 (SOCS3). Our results also demonstrated that multiple signaling cascades, including several members of the protein kinase C (PKC) family, JNK, ERK, and STAT3, play critical roles in the activation of MMP-2 and Bcl-2 mediated by NS4B. Further studies revealed that the C-terminal domain (CTD) of NS4B is sufficient for the activation of STAT3, JNK, ERK, MMP-2, and Bcl-2. We also showed that amino acids 227 to 250 of NS4B are essential for regulation of STAT3, JNK, ERK, MMP-2, and Bcl-2, and among them, three residues (237L, 239S, and 245L) are crucial for this regulation. Thus, we revealed a novel mechanism underlying HCV pathogenesis in which multiple intracellular signal cascades are cooperatively involved in the activation of two important cellular factors, MMP-2, and Bcl-2, in response to HCV infection.Journal of Virology 09/2012; · 5.08 Impact Factor
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ABSTRACT: In neuroendocrine cells, prohormones move from the endoplasmic reticulum to the Golgi complex (GC), where they are sorted and packed into secretory granules. The GC is considered the central station of the secretory pathway of proteins and lipids en route to their final destination. In most mammalian cells, it is formed by several stacks of cisternae connected by tubules, forming a continuous ribbon. This organelle shows an extraordinary structural and functional complexity, which is exacerbated by the fact that its architecture is cell type specific and also tuned by the functional status of the cell. It is, indeed, one the most beautiful cellular organelles and, for that reason, perhaps the most extensively photographed by electron microscopists. In recent decades, an exhaustive dissection of the molecular machinery involved in membrane traffic and other Golgi functions has been carried out. Concomitantly, detailed morphological studies have been performed, including 3D analysis by electron tomography, and the precise location of key proteins has been identified by immunoelectron microscopy. Despite all this effort, some basic aspects of Golgi functioning remain unsolved. For instance, the mode of intra-Golgi transport is not known, and two opposing theories (vesicular transport and cisternal maturation models) have polarized the field for many years. Neither of these theories explains all the experimental data so that new theories and combinations thereof have recently been proposed. Moreover, the specific role of the small vesicles and tubules which surround the stacks needs to be clarified. In this review, we summarize our current knowledge of the Golgi architecture in relation with its function and the mechanisms of intra-Golgi transport. Within the same framework, the characteristics of the GC of neuroendocrine cells are analyzed.Frontiers in Endocrinology 01/2013; 4:41.