Search

Colorectal cancer (CRC) is a major life-threatening disease, being the third most common cancer and a leading cause of death worldwide. Enhanced adiposity, particularly visceral fat, is a major risk factor for CRC, and obesity-associated alterations in metabolic, inflammatory and immune profiles in visceral adipose tissue (VAT) strongly contribute to promoting or sustaining intestinal carcinogenesis. The role of diet and nutrition in obesity and CRC has been extensively demonstrated, and AT represents the main place where diet-induced signals are integrated. Among the factors introduced with diet and processed or enriched in AT, ω3/ω6 polyunsaturated fatty acids (PUFAs) are endowed with pro- or anti-inflammatory properties and have been shown to exert either promoting or protective roles in CRC. In this study, we investigated the impact of ex vivo exposure to the ω3 and ω6 PUFAs docosahexaenoic and arachidonic acids on VAT adipocyte whole transcription in healthy lean, obese and CRC-affected individuals. High-throughput sequencing of protein-coding and long non-coding RNAs allowed us to identify specific pathways and regulatory circuits controlled by PUFAs and highlighted an impaired responsiveness of obese and CRC-affected individuals as compared to the strong response observed in healthy lean subjects. This further supports the role of healthy diets and balanced ω3/ω6 PUFA intake in the primary prevention of obesity and cancer., Competing Interests: The authors declare no conflicts of interest.

Colorectal cancer (CRC) is a leading cause of death worldwide. Despite advances in surgical and therapeutic management, tumor metastases and resistance to therapy still represent major hurdles. CRC risk is highly modifiable by lifestyle factors, including diet, which strongly influences both cancer incidence and related mortality. Galectin-3 (Gal-3) is a multifaceted protein involved in multiple pathophysiological pathways underlying chronic inflammation and cancer. Its versatility is given by the ability to participate in a wide range of tumor-promoting processes, including cell-cell/cell-matrix interactions, cell growth regulation and apoptosis, and the immunosuppressive tumor microenvironment. This review provides an updated summary of preclinical and observational human studies investigating the pathogenetic role of Gal-3 in intestinal inflammation and CRC, as well as the potential of Gal-3 activity inhibition by plant-source food-derived bioactive compounds to control CRC onset/growth. These studies highlight both direct and immuno-mediated effects of Gal-3 on tumor growth and invasiveness and its potential role as a CRC prognostic biomarker. Substantial evidence indicates natural food-derived Gal-3 inhibitors as promising candidates for CRC prevention and therapy. However, critical issues, such as their bioavailability and efficacy, in controlled human studies need to be addressed to translate research progress into clinical applications.

Colorectal cancer (CRC) is a major cancer type and a leading cause of death worldwide. Despite advances in therapeutic management, the current medical treatments are not sufficient to control metastatic disease. Treatment-related adverse effects and drug resistance strongly contribute to therapy failure and tumor recurrence. Combination therapy, involving cytotoxic treatments and non-toxic natural compounds, is arousing great interest as a promising more effective and safer alternative. Polyphenols, a heterogeneous group of bioactive dietary compounds mainly found in fruit and vegetables, have received great attention for their capacity to modulate various molecular pathways active in cancer cells and to affect host anticancer response. This review provides a summary of the most recent (i.e., since 2016) preclinical and clinical studies using polyphenols as adjuvants for CRC therapies. These studies highlight the beneficial effects of dietary polyphenols in combination with cytotoxic drugs or irradiation on both therapy outcome and drug resistance. Despite substantial preclinical evidence, data from a few pilot clinical trials are available to date with promising but still inconclusive results. Larger randomized controlled studies and polyphenol formulations with improved bioavailability are needed to translate the research progress into clinical applications and definitively prove the added value of these molecules in CRC management.

Colorectal cancer (CRC) is among the major threatening diseases worldwide, being the third most common cancer, and a leading cause of death, with a global incidence expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is a major risk factor for the development of several tumours, including CRC, and represents an important indicator of incidence, survival, prognosis, recurrence rates, and response to therapy. The obesity-associated low-grade chronic inflammation is thought to be a key determinant in CRC development, with the adipocytes and the adipose tissue (AT) playing a significant role in the integration of diet-related endocrine, metabolic, and inflammatory signals. Furthermore, AT infiltrating immune cells contribute to local and systemic inflammation by affecting immune and cancer cell functions through the release of soluble mediators. Among the factors introduced with diet and enriched in AT, fatty acids (FA) represent major players in inflammation and are able to deeply regulate AT homeostasis and immune cell function through gene expression regulation and by modulating the activity of several transcription factors (TF). This review summarizes human studies on the effects of dietary FA on AT homeostasis and immune cell functions, highlighting the molecular pathways and TF involved. The relevance of FA balance in linking diet, AT inflammation, and CRC is also discussed. Original and review articles were searched in PubMed without temporal limitation up to March 2021, by using fatty acid as a keyword in combination with diet, obesity, colorectal cancer, inflammation, adipose tissue, immune cells, and transcription factors.

Obesity, and the obesity-associated inflammation, represents a major risk factor for the development of chronic diseases, including colorectal cancer (CRC). Dysfunctional visceral adipose tissue (AT) is now recognized as key player in obesity-associated morbidities, although the biological processes underpinning the increased CRC risk in obese subjects are still a matter of debate. Recent findings have pointed to specific alterations in the expression pattern of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), as mechanisms underlying dysfunctional adipocyte phenotype in obesity. Nevertheless, the regulatory networks and interrelated processes relevant for adipocyte functions, that may contribute to a tumor-promoting microenvironment, are poorly known yet. To this end, based on RNA sequencing data, we identified lncRNAs and miRNAs, which are aberrantly expressed in visceral adipocytes from obese and CRC subjects, as compared to healthy lean control, and validated a panel of modulated ncRNAs by real-time qPCR. Furthermore, by combining the differentially expressed lncRNA and miRNA profiles with the transcriptome analysis dataset of adipocytes from lean and obese subjects affected or not by CRC, lncRNA-miRNA-mRNA adipocyte networks were defined for obese and CRC subjects. This analysis highlighted several ncRNAs modulation that are common to both obesity and CRC or unique of each disorder. Functional enrichment analysis of network-related mRNA targets, revealed dysregulated pathways associated with metabolic processes, lipid and energy metabolism, inflammation, and cancer. Moreover, adipocytes from obese subjects affected by CRC exhibited a higher complexity, in terms of number of genes, lncRNAs, miRNAs, and biological processes found to be dysregulated, providing evidence that the transcriptional and post-transcriptional program of adipocytes from CRC patients is deeply affected by obesity. Overall, this study adds further evidence for a central role of visceral adipocyte dysfunctions in the obesity-cancer relationship., (Copyright © 2020 Tait, Baldassarre, Masotti, Calura, Martini, Varì, Scazzocchio, Gessani and Del Cornò.)

β-glucans represent a heterogeneous group of naturally occurring and biologically active polysaccharides found in many kinds of edible mushrooms, baker's yeast, cereals and seaweeds, whose health-promoting effects have been known since ancient times. These compounds can be taken orally as food supplements or as part of daily diets, and are safe to use, nonimmunogenic and well tolerated. A main feature of β-glucans is their capacity to function as biological response modifiers, exerting regulatory effects on inflammation and shaping the effector functions of different innate and adaptive immunity cell populations. The potential to interfere with processes involved in the development or control of cancer makes β-glucans interesting candidates as adjuvants in antitumor therapies as well as in cancer prevention strategies. Here, the regulatory effects of dietary β-glucans on human innate immunity cells are reviewed and their potential role in cancer control is discussed., Competing Interests: The authors declare no conflicts of interest.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the world. Patterns and trends in CRC incidence and mortality correlate with increasing adoption of Western lifestyles and with the overweight/obesity epidemic. Both genetic background and a range of modifiable environmental/lifestyle factors play a role in CRC etiology. Among these the links of body weight, dietary patterns and physical activity (PA) behavior with CRC risk are some of the strongest for any type of cancer, with a different impact in women and men. Nonetheless, gender disparities still represent a neglected aspect of CRC management. This review sheds light on gender-related association of obesity and different dietary/PA habits with CRC risk, highlighting the importance of lifestyle modifications in the prevention of this neoplastic disease. In this scenario, intervention studies are strongly recommended to define the most effective dietary/PA regimens for primary prevention of cancer in women and men., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Obesity, a low-grade inflammatory condition, represents a major risk factor for the development of several pathologies including colorectal cancer (CRC). Although the adipose tissue inflammatory state is now recognized as a key player in obesity-associated morbidities, the underlying biological processes are complex and not yet precisely defined. To this end, we analyzed transcriptome profiles of human visceral adipocytes from lean and obese subjects affected or not by CRC by RNA sequencing ( n = 6 subjects/category), and validated selected modulated genes by real-time qPCR. We report that obesity and CRC, conditions characterized by the common denominator of inflammation, promote changes in the transcriptional program of adipocytes mostly involving pathways and biological processes linked to extracellular matrix remodeling, and metabolism of pyruvate, lipids and glucose. Interestingly, although the transcriptome of adipocytes shows several alterations that are common to both disorders, some modifications are unique under obesity (e.g., pathways associated with inflammation) and CRC (e.g., TGFβ signaling and extracellular matrix remodeling) and are influenced by the body mass index (e.g., processes related to cell adhesion, angiogenesis, as well as metabolism). Indeed, cancer-induced transcriptional program is deeply affected by obesity, with adipocytes from obese individuals exhibiting a more complex response to the tumor. We also report that in vitro exposure of adipocytes to ω3 and ω6 polyunsaturated fatty acids (PUFA) endowed with either anti- or pro-inflammatory properties, respectively, modulates the expression of genes involved in processes potentially relevant to carcinogenesis, as assessed by real-time qPCR. All together our results suggest that genes involved in pyruvate, glucose and lipid metabolism, fibrosis and inflammation are central in the transcriptional reprogramming of adipocytes occurring in obese and CRC-affected individuals, as well as in their response to PUFA exposure. Moreover, our results indicate that the transcriptional program of adipocytes is strongly influenced by the BMI status in CRC subjects. The dysregulation of these interrelated processes relevant for adipocyte functions may contribute to create more favorable conditions to tumor establishment or favor tumor progression, thus linking obesity and colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of death, with burden expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is associated with increased cancer incidence representing an important indicator of survival, prognosis, recurrence rates, and response to therapy for several tumors including CRC. Compelling evidence has been achieved that the low-grade chronic inflammation characterizing obesity represents a main factor that can favor carcinogenesis. Adipocytes and adipose tissue (AT) infiltrating immune cells contribute to obesity-related inflammation by releasing soluble factors affecting, both locally and systemically, the function of several cell types, including immune and cancer cells. The unbalanced production of immune mediators as well as the profound changes in the repertoire and activation state of immune cells in AT of obese subjects represent key events in the processes that set the basis for a pro-tumorigenic microenvironment. AT harbors a unique profile of immune cells of different origin that play an important role in tissue homeostasis. Among these, tissue-resident innate lymphocytes are emerging as important AT components whose depletion/aberrant activation occurring in obesity could have an impact on inflammation and immune-surveillance against tumors. However, a direct link between obesity-induced dysfunction and cancer development has not been demonstrated yet. In this review, we provide an overview of human obesity- and CRC-induced alterations of blood and adipose tissue-associated innate lymphocytes, and discuss how the adipose tissue microenvironment in obesity might influence the development of CRC.

Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this association remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (T reg ) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like, γδ T, and T reg cell populations in VAT and blood of healthy lean subjects revealed that CD56 hi NK and OX40 + T reg cells are more abundant in VAT with respect to blood. Conversely, CD56 dim NK and total T reg cells are most present in the circulation, while γδ T lymphocytes are uniformly distributed in the two compartments. Interestingly, a reduced frequency of circulating activated T reg cells, and a concomitant preferential enrichment of OX40-expressing T reg cells in VAT, were selectively observed in obese (Ob) subjects, and directly correlated with body mass index. Likewise, CRC patients were characterized by a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected individuals shared a significant reduction of the Vγ9Vδ2/γδ T cell ratio at systemic level. The alterations in the relative proportions of T reg and NKT-like cells in VAT were found to correlate with the content of pro- and anti-inflammatory polyunsaturated fatty acids (PUFA), respectively. Overall, these results provide evidence for distinct alterations of the immune cell repertoire in the periphery with respect to the VAT microenvironment that uniquely characterize or are shared by different inflammatory conditions, such as obesity and CRC, and suggest that VAT PUFA composition may represent one of the factors that contribute to shape the immune phenotypes.

Environmental and lifestyle factors, including diet and nutritional habits have been strongly linked to colorectal cancer (CRC). Of note, unhealthy dietary habits leading to adiposity represent a main risk factor for CRC and are associated with a chronic low-grade inflammatory status. Inflammation is a hallmark of almost every type of cancer and can be modulated by several food compounds exhibiting either protective or promoting effects. However, in spite of an extensive research, the underlying mechanisms by which dietary patterns or bioactive food components may influence tumor onset and outcome have not been fully clarified yet. Growing evidence indicates that diet, combining beneficial substances and potentially harmful ingredients, has an impact on the expression of key regulators of gene expression such as the non-coding RNA (ncRNA). Since the expression of these molecules is deranged in chronic inflammation and cancer, modulating their expression may strongly influence the cancer phenotype and outcomes. In addition, the recently acquired knowledge on the existence of intricate inter-kingdom communication networks, is opening new avenues for a deeper understanding of the intimate relationships linking diet to CRC. In this novel scenario, diet-modulated ncRNA may represent key actors in the interaction between plant and animal kingdoms, capable of influencing disease onset and outcome. In this review, we will summarize the studies demonstrating a link between bioactive food components, including food-derived, microbiota-processed, secondary metabolites, and host ncRNA. We will focus on microRNA, highlighting how this plant/animal inter-kingdom cross-talk may have an impact on CRC establishment and progression.

Obesity is a low-grade chronic inflammatory state representing an important risk factor for colorectal cancer (CRC). Adipocytes strongly contribute to inflammation by producing inflammatory mediators. In this study we investigated the role of human visceral fat adipocytes in regulating the functions of innate immunity cells. Adipocyte-conditioned media (ACM) from obese (n = 14) and CRC (lean, n = 14; obese, n = 13) subjects released higher levels of pro-inflammatory/immunoregulatory factors as compared to ACM from healthy lean subjects (n = 13). Dendritic cells (DC), differentiated in the presence of ACM from obese and CRC subjects, expressed elevated levels of the inhibitory molecules PD-L1 and PD-L2, and showed a reduced IL-12/IL-10 ratio in response to both TLR ligand- and γδ T lymphocyte-induced maturation. Furthermore, CRC patient-derived ACM inhibited DC-mediated γδ T cell activation. The immunosuppressive signals delivered by ACM from obese and CRC individuals were associated with a pro-inflammatory secretory and ω6 polyunsaturated fatty acid profile of adipocytes. Interestingly, STAT3 activation in adipocytes correlated with dihomo-γlinolenic acid content and was further induced by arachidonic acid, which conversely down-modulated PPARγ. These results provide novel evidence for a cross-talk between human adipocytes and innate immunity cells whose alteration in obesity and CRC may lead to immune dysfunctions, thus setting the basis for cancer development.

Highly active antiretroviral therapy has significantly improved the prognosis of HIV-infected subjects. However, patients treated long term still manifest increased mortality and, even with undetectable plasma viremia, often experience persistent immune activation. Furthermore, liver-related mortality is now the most common cause of non-AIDS-related death in HIV-infected individuals on highly active antiretroviral therapy through accelerated fibrosis progression. TLRs are the first line of the host response to pathogens and play an important role in human host defense against viruses through sensing of viral structural proteins. Growing evidence points to TLR4 as a key player in chronic immune activation, HIV recognition/replication, and liver fibrosis progression, suggesting that HIV triggering of TLR4 may dictate some aspects of the multifaceted AIDS pathogenesis. In this study, we provide evidence for an interplay between host TLR4 and HIV-1 gp120 in human monocyte-derived macrophages and hepatic stellate cells, leading to intracellular pathways and biologic activities that mediate proinflammatory and profibrogenic signals. Finally, we hypothesize that CCR5 and TLR4 are likely part of a common receptor cluster, as the blocking of CCR5 by specific antagonists impairs the macrophage capacity to produce chemokines in response to LPS. Chronic immune activation and liver fibrosis remain important obstacles for highly active antiretroviral therapy success. Thus, the identification of gp120-TLR4 axis as a novel determinant of immune system and hepatic stellate cell biology opens new perspectives to the management of HIV infection and disease., (© Society for Leukocyte Biology.)

Marked changes in socioeconomic status, cultural traditions, population growth, and agriculture have been affecting diets worldwide. Nutrition is known to play a pivotal role in the pathogenesis of several chronic diseases, and the use of bioactive food compounds at pharmacologic doses is emerging as a preventive and/or therapeutic approach to target metabolic dysregulations occurring in aging, obesity-related chronic diseases, and cancer. Only recently have data on the effects of specific nutrients or food on the immune system become available, and studies regarding the human immune system are still in their infancy. Beyond providing essential nutrients, diet can actively influence the immune system. Understanding how diet and nutritional status influence the innate and adaptive arms of our immune system represents an area of scientific need, opportunity, and challenge. The insights gleaned should help to address several pressing global health problems. Recently, biologically active polyphenols, which are widespread constituents of fruit and vegetables, have gained importance as complex regulators of various cellular processes, critically involved in the maintenance of body homeostasis. This review outlines the potential effects of polyphenols on the function of dendritic cells (DCs), key players in the orchestration of the immune response. Their effects on different aspects of DC biology including differentiation, maturation, and DC capacity to shift immune response toward tolerance or immune activation will be outlined.

The Toll-like receptors are the first line of the host response to pathogens, representing an essential component of the innate and adaptive immune response. They recognize different pathogens and trigger responses directed at eliminating the invader and at developing immunologic long-term memory, ultimately affecting viral pathogenesis. In viral infections, sensing of nucleic acids and/or viral structural proteins generally induces a protective immune response. Thus, it is not surprising that many viruses have developed strategies to evade or counteract signaling through the Toll-like receptor pathways, to survive the host defense machinery and ensure propagation. Thus, Toll-like receptor engagement can also be part of viral pathogenic mechanisms. Evidence for a direct interaction of Toll-like receptors with human immunodeficiency virus type 1 (HIV-1) structures has started to be achieved, and alterations of their expression and function have been described in HIV-1-positive subjects. Furthermore, Toll-like receptor triggering by bacterial and viral ligands have been described to modulate HIV-1 replication and host response, leading to protective or detrimental effects. This review covers major advances in the field of HIV-1 interplay with Toll-like receptors, focusing on human myeloid cells (e.g., monocytes/macrophages and dendritic cells). The role of this interaction in the dysregulation of myeloid cell function and in dictating aspects of the multifaceted pathogenesis of acquired immunodeficiency syndrome will be discussed., (© Society for Leukocyte Biology.)

Lactoferrin (LF) exhibits a wide range of immunomodulatory activities including modulation of cytokine and chemokine secretion. In this study, we demonstrate that bovine LF (bLF) up-modulates, in a concentration- and time-dependent manner, CCL1 secretion in monocytes (Mo) at the early stage of differentiation toward dendritic cells (DCs), and in fully differentiated immature Mo-derived DCs (MoDCs). In both cell types, up-modulation of CCL1 secretion is an early event following bLF-mediated enhanced accumulation of CCL1 transcripts. Notably, bLF-mediated up-regulation of CCL1 involves the engagement of distinct surface receptors in MoDCs and their Mo precursors. We show that bLF-mediated engagement of CD36 contributes to CCL1 induction in differentiating Mo. Conversely, toll-like receptor (TLR)2 blocking markedly reduces bLF-induced CCL1 production in MoDCs. These findings add further evidence for cell-specific differential responses elicited by bLF through the engagement of distinct TLRs and surface receptors. Furthermore, the different responses observed at early and late stages of Mo differentiation towards DCs may be relevant in mediating bLF effects in specific body districts, where these cell types may be differently represented in physiopathological conditions.

Background: MicroRNAs (miRs) are an abundant class of small non-coding RNAs (~22 nt) that reprogram gene expression by targeting mRNA degradation and translational disruption. An emerging concept implicates miR coupling with transcription factors in myeloid cell development and function, thus contributing to host defense and inflammation. The important role that these molecules play in the pathogenesis of HIV-1 is only now emerging., Results: We provide evidence that exposure of monocyte-derived dendritic cells (MDDCs) to recombinant HIV-1 R5 gp120, but not to CCR5 natural ligand CCL4, influences the expression of a panel of miRs (i.e., miR-21, miR-155 and miR-181b) regulated by STAT3 and potentially targeting genes belonging to the STAT3 signaling pathway. The blockage of gp120-induced STAT3 activation impairs gp120 capacity to modulate the expression level of above mentioned miRs. Predictive analysis of miR putative targets emphasizes that these miRs share common target genes. Furthermore, gene ontology and pathway enrichment analysis outline that these genes mainly belong to biological processes related to regulation of transcription, in a complex network of interactions involving pathways relevant to HIV-DC interaction., Conclusions: Overall, these results point to gp120-triggered modulation of miR expression via STAT3 activation as a novel molecular mechanism exploited by HIV-1 to affect DC biology and thus modulate the immune response through complex regulatory loops involving, at the same time, miRs and transcription factors.

Unlabelled: Dendritic cells (DCs) are fundamental for the initiation of immune responses and are important players in AIDS immunopathogenesis. The modulation of DC functional activities represents a strategic mechanism for HIV-1 to evade immune surveillance. Impairment of DC function may result from bystander effects of HIV-1 envelope proteins independently of direct HIV-1 infection. In this study, we report that exposure of immature monocyte-derived DCs (MDDCs) to HIV-1 R5 gp120 resulted in the CCR5-dependent production of interleukin-6 (IL-6) via mitogen-activated protein kinase (MAPK)/NF-κB pathways. IL-6 in turn activated STAT3 by an autocrine loop. Concomitantly, gp120 promoted an early activation of STAT3 that further contributed to IL-6 induction. This activation paralleled a concomitant upregulation of the STAT3 inhibitor PIAS3. Notably, STAT3/IL-6 pathway activation was not affected by the CCR5-specific ligand CCL4. These results identify STAT3 as a key signaling intermediate activated by gp120 in MDDCs and highlight the existence of a virus-induced dysregulation of the IL-6/STAT3 axis. HIV-1 gp120 signaling through STAT3 may provide an explanation for the impairment of DC function observed upon HIV exposure., Importance: This study provides new evidence for the molecular mechanisms and signaling pathways triggered by HIV-1 gp120 in human DCs in the absence of productive infection, emphasizing a role of aberrant signaling in early virus-host interaction, contributing to viral pathogenesis. We identified STAT3 as a key component in the gp120-mediated signaling cascade involving MAPK and NF-κB components and ultimately leading to IL-6 secretion. STAT3 now is recognized as a key regulator of DC functions. Thus, the identification of this transcription factor as a signaling molecule mediating some of gp120's biological effects unveils a new mechanism by which HIV-1 may deregulate DC functions and contribute to AIDS pathogenesis., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Polyphenols have been shown to exhibit anti-inflammatory, anti-oxidant and immunomodulatory activities. However, the effects of anthocyanins, flavonoids of great nutritional interest, in particular of their metabolite protocatechuic acid (PCA) on the phenotypic and functional maturation of human dendritic cells (DCs) are still largely unknown. In this study, we report that PCA is efficiently taken up and accumulated in human monocyte-derived DCs (MD-DCs). PCA exposure of MD-DCs markedly impaired the production of proinflammatory cytokines and chemokines (i.e. IL-6, IL-8 and CCL2) in response to bacterial endotoxin and leptin, and down-regulated the lipopolysaccharide (LPS)-induced migratory response of MD-DCs to CCL19. Conversely, the phenotypic profile induced by LPS-mediated activation as well as IL-12 production was not affected. Interestingly, we found that PPARγ is a main factor in the PCA-induced effects as blocking its activity abolish PCA capacity to down-regulate IL-6 and IL-8, but not CCL2, secretion and to inhibit MD-DC migration. In keeping with this observation, cytosol to nucleus translocation and PPARγ activity were found to be directly stimulated by PCA exposure of MD-DCs. These novel findings provide new insight into the immunoregulatory effects of polyphenol metabolites in DCs opening new perspectives on their potential application in the prevention of acute and chronic inflammatory diseases., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Type I interferons (IFNs) are pleiotropic cytokines, initially described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer, viral infections and chronic inflammatory diseases. It is now well established that IFN action mostly relies on their ability to modulate host innate and adaptive immune responses. Work in recent years has begun to elucidate the mechanisms by which type I IFNs modify the immune response, and this is now recognized to be due to effects on multiple cell types, including monocytes, dendritic cells (DCs), NK cells, T and B lymphocytes. An ensemble of results from both animal models and in vitro studies emphasized the key role of type I IFNs in the development and function of DCs, suggesting the existence of a natural alliance between these cytokines and DCs in linking innate to adaptive immunity. The identification of IFN signatures in DCs and their dysregulation under pathological conditions will therefore be pivotal to decipher the complexity of this DC-IFN interaction and to better exploit the therapeutic potential of these cells.

MicroRNAs (miRNAs) are a class of small noncoding RNAs acting as post-transcriptional gene expression regulators in many physiological and pathological conditions. During the last few years, many novel mammalian miRNAs have been predicted experimentally with bioinformatics approaches and validated by next-generation sequencing. Although these strategies have prompted the discovery of several miRNAs, the total number of these genes still seems larger. Here, by exploiting the species conservation of human, mouse, and rat hairpin miRNAs, we discovered a novel rat microRNA, mir-155. We found that mature miR-155 is overexpressed in rat spleen myeloid cells treated with LPS, similarly to humans and mice. Rat mir-155 is annotated only on the alternate genome, suggesting the presence of other "hidden" miRNAs on this assembly. Therefore, we comprehensively extended the homology search also to mice and humans, finally validating 34 novel mammalian miRNAs (two in humans, five in mice, and up to 27 in rats). Surprisingly, 15 of these novel miRNAs (one for mice and 14 for rats) were found only on the alternate and not on the reference genomic assembly. To date, our findings indicate that the choice of genomic assembly, when mapping small RNA reads, is an important option that should be carefully considered, at least for these animal models. Finally, the discovery of these novel mammalian miRNA genes may contribute to a better understanding of already acquired experimental data, thereby paving the way to still unexplored investigations and to unraveling the function of miRNAs in disease models.

Toll-like receptor (TLR) 3 recognizes double-stranded RNA and triggers the production of type 1 interferon and inflammatory cytokines/chemokines. Its engagement in dendritic cells (DCs) induces their maturation into potent immunostimulatory cells endowed with the capacity to efficiently cross-prime T lymphocytes. Owing to these properties, TLR3 agonists are currently under investigation as promising adjuvants in DC-based immunotherapy protocols for the treatment of viral and neoplastic diseases. Thus, a detailed understanding of the cascade of events specifically triggered in DCs upon engagement of this receptor is of great interest in translational research. In this review, we summarize the current knowledge on TLR3 signalling in DCs and highlight similarities and differences with respect to other cell types., (Copyright 2010 Elsevier GmbH. All rights reserved.)

Toll-like receptor (TLR) signaling activation by pathogens is critical to the induction of immune responses, and demands tight regulation. We describe in this study that CC chemokine ligand 2 (CCL2) secretion triggered by TLR4 or TLR8 engagement is strongly inhibited upon simultaneous activation of both TLRs in human monocyte-derived dendritic cells (DCs). Impaired CCL2 secretion occurs concomitantly to interleukin-12 up-regulation, being part of a complex regulatory circuit ensuring optimal T helper type 1 polarization. Interestingly, triggering selected TLRs or their combinations differently affects nuclear factor-kappaB p65 activation and microRNA expression. Overall, these results indicate that CCL2 supplies an important immunomodulatory role to DCs, and may contribute to dictate the cytokine profile in T helper type 1 responses induced by DCs.

Exposure to aldrithiol-2-inactivated human immunodeficiency virus type 1 or gp120, but not gp41, triggered alpha interferon (IFN-alpha), CC chemokine ligand 2 (CCL2), CCL3, and CCL4 production in human plasmacytoid dendritic cells (DCs) but not in myeloid DCs (M-DCs) or monocyte-derived DCs from the same donors. The nonresponsiveness of M-DCs for IFN-alpha/beta production was a general feature specific to these cells, as they also failed to produce it in response to inactivated influenza virus, poly(I-C), lipopolysaccharide, Staphylococcus aureus Cowans I, or CD40L. The different capacities of circulating DC subsets to produce immune mediators in response to most stimuli argue for a different role for these cells in the regulation of innate immunity to pathogens.

Antigen presenting cell (APC) function is central to the development of an effective anti-viral immune response. Among APC, monocytes, macrophages and dendritic cells (DC) form the principal non-T cell compartment involved in in vivo HIV infection, and these cells play important and well-established roles in multiple aspects of viral pathogenesis. HIV infection may result in APC defects, which could ultimately contribute to the loss of CD4+ T cell responses observed early in HIV infection, when the CD4+ T cell number is still within the normal range. Extensive in vitro studies have demonstrated that the envelope glycoproteins of HIV-1 exert profound influences on various cell populations of the immune system, including hematopoietic progenitors, T and B lymphocytes, monocytes/ macrophages and DC, as well as on neuronal cells. The demonstration of the presence of envelope proteins both free in the circulation and bound to the surface of CD4+ cells suggests that gp120 interactions with non-infected cells can influence cellular functions in vivo, thus contributing to the immunopathogenesis of AIDS. This paper provides an overview of the present knowledge on gp120 binding, signal transduction triggering and interference with macrophage and DC functions and it highlights the importance of this interaction in the pathogenesis of AIDS.

We characterized the IL-12 response of mouse macrophages in terms of modulation of IFN-gamma production by cytokines (IFN-alpha and IL-18) and regulation of IL-12 receptor expression. Beta1 and beta2 IL-12R chain mRNA expression increased with time in culture in the absence of exogenous stimulation, with concomitant acquisition of responsiveness to IL-12 for IFN-gamma production. Expression of the IL-12R beta1 chain mRNA was increased further following IL-12 treatment as a consequence of IFN-gamma expression. IL-12 response was regulated differentially by IFN-alpha and IL-18. Neutralization of endogenous type I IFN increased IFN-gamma secretion, whereas exogenous IFN-alpha reduced it. In contrast, IL-18 enhanced IFN-gamma mRNA accumulation and IFN-gamma secretion in IL-12-stimulated, but not -untreated, cultures. The opposite effects exerted by IFN-alpha and IL-18 mirror their mutual capacity of regulating-in a negative or positive manner, respectively-the expression of the IL-12R beta1 chain. We suggest that differential regulation of IL-12 response by IFN-alpha and IL-18 can represent previously unrecognized regulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages.

The monocyte/macrophage lineage represents heterogeneous cell populations characterized by major differences in the phenotype and functional activities. These cells are a major source of soluble factors, such as cytokines and chemokines, which can both affect HIV replication and AIDS pathogenesis. Although monocytes/macrophages are unanimously considered important targets of HIV-1 infection, the HIV-induced alterations in their physiological functions at different stages of differentiation are still matter of debate. In this article, we review our data on the regulation of chemokine/cytokine network with regard to macrophage differentiation and HIV-1 infection, in comparison with studies from other groups. The ensemble of the results emphasizes that: 1) macrophages markedly differ with respect to monocytes for a variety of responses potentially important in the pathogenesis of HIV infection; and 2) the experimental conditions can influence the HIVmonocyte/macrophage interactions, reflecting the possible in vivo existence of a spectrum of responses among macrophage populations.

Superstructural features of the Kluyveromyces lactis chromosome 1 (KlCEN1) and of the Saccharomyces cerevisiae chromosome 6 (SCEN6) centromeric DNAs were evaluated using a theoretical method, developed by our group, and experimentally measured by gel electrophoretic retardation. Both methods show that, in spite of the remarkable AT richness of the two centromeric sequences, their curvature is not very high. However the peculiar sequence features of the two centromeres allow to organize highly stable nucleosomes, with a free energy about that of the nucleosome formed on the 5S RNA gene. The good agreement between experimental and theoretical evaluation of nucleosome free energies as well as of their multiple positioning shows that in centromeres both DNA curvature and flexibility are relevant in determining nucleosomal features.