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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.

Introduction Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. Methods RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Discussion Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. Ethics and dissemination The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.

Background: Patients presenting with upper motor neuron (UMN) signs may widely diverge in prognosis, ranging from amyotrophic lateral sclerosis (ALS) to primary lateral sclerosis (PLS) and hereditary spastic paraplegia (hSP). Neurofilaments are emerging as potential diagnostic and prognostic biomarkers for ALS, but the diagnosis of UMN syndromes still relies mostly on clinical long-term observation and on familiarity or genetic confirmation. Objectives: To test whether phosphorylated neurofilament heavy chain (pNfH) may discriminate different UMN syndromes at diagnosis and to test their prognostic role among these diseases. Methods: We measured the cerebrospinal fluid (CSF) and serum pNfH of 30 patients presenting with UMN signs and diagnosed with ALS, hSP, and PLS, plus 9 healthy controls (HC). Results: ALS patients had higher levels of pNfH in CSF and serum compared to HC (p < 0.001 and p < 0.001 in CSF and serum, respectively) and PLS (p = 0.015 and p = 0.038) and hSP (p = 0.003 and p = 0.001) patients. PLS and hSP patients had similar CSF and serum pNfH concentrations, but a higher CSF pNfH concentration, compared to HC (p = 0.002 and p = 0.003 for PLS and hSP, respectively). Receiver operating characteristic curves for discriminating ALS from PLS and hSP showed an area under the curve of 0.79 for CSF and 0.81 for serum. In multivariable survival analysis including relevant clinical factors CSF pNfH represented the strongest variable predicting survival (HR 40.43; 95% CI 3.49–467.79, p = 0.003) independently of clinical group. Conclusions: Despite some statistical instability of the results due to limitations in sample size, our study supports the role of CSF pNfH as a prognostic biomarker for motor neuron diseases presenting with UMN signs. A potential power to discriminate between ALS and other UMN syndromes at presentation, and between all of the examined MND and HC, has been detected for both CSF and serum pNfH.

Tesi di Laurea in Chimica riguardante l'analisi spettrofotometrica e morfologica dei pigmenti contenuti in un inchiostro verde per tatuaggi

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.

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 receptor. 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.

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.

Dendritic cells (DC) are an attractive target for therapeutic manipulation of the immune system to enhance insufficient immune responses, such those occurring in cancer, or to dampen dangerous responses in allergic and autoimmune diseases. Main goal of this study was to manipulate human monocyte-derived DC (MDDC) function by silencing STAT3, since this transcription factor plays a key role as a negative regulator of immune surveillance, and is strongly involved in inflammation. STAT3 silencing did not affect the immunophenotype of both immature and toll-like receptor (TLR) ligand-matured DC. However, an altered cytokine secretion profile, characterized by lower IL10 and higher IL12 and TNFα levels, was observed in silenced DC with respect to control cells upon TLR triggering. Accordingly, STAT3 silenced MDDC promoted a higher IFNγ production by CD4+ naive T cells. Furthermore, STAT3 silencing in MDDC favored the activation of γδ T lymphocytes, an immune cell population with important antitumor effector activities. This effect was at least in part mediated by the increased IL12 production by silenced cells. STAT3 silencing also increased the levels of CCL4, a CCR5-binding chemokine known to be involved in T helper 1 (Th1) cell recruitment. Altogether these results strengthen the role of STAT3 as a critical check point of the suppression of Th1 responses, unraveling its potential to dampen DC capability to both induce and recruit different IFNγ producing T lymphocyte subsets.

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.

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.

Diet composition may affect the onset and progression of chronic degenerative diseases, including cancer, whose pathogenesis relies on inflammatory processes. Growing evidence indicates that diet and its components critically contribute to human health, affecting the immune system, secretion of adipokines, and metabolic pathways. Colorectal cancer (CRC) is one of the leading causes of death worldwide. Antineoplastic drugs are widely used for CRC treatment, but drug resistance and/or off-target toxicity limit their efficacy. Dietary ω3 polyunsaturated fatty acids (PUFA) have been gaining great interest in recent years as possible anti-inflammatory and anticancer agents, especially in areas such as the large bowel, where the pro-inflammatory context promotes virtually all steps of colon carcinogenesis. Growing epidemiological, experimental, and clinical evidence suggests that ω3 PUFA may play a role in several stages of CRC management exhibiting antineoplastic activity against human CRC cells, improving the efficacy of radiation and chemotherapy, ameliorating cancer-associated secondary complications, and preventing CRC recurrence. These effects are most likely related to the immunomodulatory activities of ω3 PUFA that are able to influence several aspects of the inflammatory process ranging from inflammasome activation, leukocyte recruitment, production of immune mediators to differentiation, and activation of immune cells. In this review, we will focus on the potential use of ω3 PUFA as adjuvant agents together with chemo/radiotherapy, highlighting the immunomodulatory effects most likely responsible for their beneficial effects in different stages of CRC management.

Consistent epidemiological and clinical evidence strongly indicates that chronic non-communicable diseases are largely associated with four lifestyle risk factors: inadequate diet, physical inactivity, tobacco use, and excessive alcohol use. Notably, obesity, a worldwide-growing pathological condition determined by the combination between inadequate diet and insufficient physical activity, is now considered a main risk factor for most chronic diseases. Dietary habits and physical activity are strongly influenced by gender attitudes and behaviors that promote different patterns of healthy or unhealthy lifestyles among women and men. Furthermore, different roles and unequal relations between genders strongly interact with differences in social and economic aspects as well as cultural and societal environment. Because of the complex network of factors involved in determining the risk for chronic diseases, it has been promoting a systemic approach that, by integrating sex and gender analysis, explores how sex-specific biological factors and gender-related social factors can interact to influence the health status.

Multiple host factors and their interactions with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. The virus exploits the cell-signaling networks to prepare the ground for viral replication, to affect functions of either infected or uninfected bystander cells, and to evade the immune response. These events are hallmarks of HIV-1 pathogenesis that lead toward AIDS. Phospholipases are essential mediators of intracellular and intercellular signaling. They function as phospholipid-hydrolyzing enzymes, generating many bioactive lipid mediators or second messengers, which control multiple cellular functions, thus regulating a variety of physiologic and pathophysiologic processes. These enzymes also represent important components of the cell-signaling networks exploited by HIV-1 and its proteins to favor viral replication and persistence, as well as immune response dysfunction. Although some individual phospholipases were studied in the context of HIV-1 infection, the mechanisms whereby they regulate diverse infection-associated processes, as well as the interaction among different phospholipases have yet to be fully elucidated. In this review, we discuss the principal aspects of the complex interaction between phospholipases, HIV-1, and the immune system. A thorough understanding of the signaling networks that involve phospholipases in both HIV-1–infected cells and individuals is essential to determine whether therapeutic targeting of these enzymes may represent a novel approach to control viral replication, as well as the associated inflammation and comorbidities.

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.

Alcuni dialoghi platonici, e sono tutti dialoghi importanti, presentano una particolarità. Platone sembra quasi divertirsi a svalutare il proprio stesso racconto o mostrandolo poco attendibile o presentando vere e proprie incongruenze. Nel Simposio, per esempio, tutto il dialogo tra Socrate e gli altri partecipanti al Simposio è raccontato da uno che non era presente al dialogo stesso ed a cui quest'ultimo è stato raccontato da un testimone che ha omesso diverse cose e non ricorda bene altre cose, anche perchè il racconto viene fatto più di dieci anni dopo che è avvenuto. Nel Parmenide tutto il confronto tra Parmenide e Socrate su problemi difficilissimi è raccontato da qualcuno che a sua volta l'ha sentito raccontare da una persona che era sì presente, ma che era anche giovanissimo, un adolescente, e che ora non si occupa più di filosofia, bensì di cavalli. Altro ancora di questo genere si trova in dialoghi fondamentali come il Teeteto o come il Timeo. Perchè Platone opera questa specie di auto svalutazione? In effetti egli sa benissimo che il suo lettore sa a sua volta che il problema dell'attendibilità storica non ha senso alcuno, dato che il lettore sa che i dialoghi platonici sono inventati dal loro autore. La messa in discussione dell'attendibilità storica rimanderà dunque, forse, ad una messa in discussione di un altro tipo di attendibilità, quella teoretica. Platone avverte in modo esplicito il proprio lettore, in più luoghi, di vedere nelle scritture che egli gli presenta, non già la verità, ma una copia più o meno sbiadita della verità; qui le incongruenze e la scarsa attendibilità potrebbero essere segnali attraverso i quali Platone avverte chi lo sta leggendo di non credere fino in fondo a quello che legge come espressione della verità assoluta e di prendere ciò che è stato scritto come un ombra imperfetta, come un resoconto impreciso di quella verità assoluta.

Chemokines production in monocytes/macrophages is crucial in modulating immune responses generated through Toll-like receptor (TLR)-mediated recognition of microbes. During microbial onset, multiple pathogen-associated structures can be present at infection sites, and simultaneously trigger different TLRs. We report here that TLR3, TLR4 and TLR8 engagement induce CCL1, CCL2 and CCL4 production in freshly isolated monocytes. While differentiating cells maintain the capacity to secrete CCL2 and CCL4, CCL1 is no longer induced at later differentiation stages. Although different pairs of TLR agonists have been described to synergistically induce cytokine production in different cell types, agonist combinations cooperate in reducing CCL1 and CCL2, but not CCL4 secretion in freshly isolated monocytes, and fail to rescue CCL1 production at later differentiation stages. The effects of single, but not combined, TLR engagement on chemokine expression mostly occur at transcriptional level, and are IL-10 independent. Conversely, inhibition of CCL1 secretion upon combined TLR engagement is partially rescued by blocking IL-23. A different chemotactic activity of monocyte-conditioned medium on blood mononuclear cells as well as antigen uptake capacity of TLR agonist activated monocytes parallel the regulated production of chemokines. Overall, these findings indicate that simultaneous engagement of TLRs may lead to different patterns of chemokine expression depending on cellular differentiation state, chemokine, and TLR agonist combination. These different responses may be relevant for the distinct but complementary functions of monocytes and macrophages in the immune response, and may have important implications for the therapeutic manipulation of the innate immune system.

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.

Lactoferrin (Lf) is a mammalian exclusive protein widely distributed in milk and exocrine secretions exhibiting multifunctional properties. Many of the proven or proposed functions of Lf, apart from its iron binding activity, depend on its capacity to bind to other macromolecules. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, the interplay between Lf and LPS is complex, and may result in different outcomes, including both suppression of the inflammatory response and immune activation. These findings are critically relevant in the development of Lf-based therapeutic interventions in humans. Understanding the molecular basis and functional consequences of Lf-LPS interaction will provide insights for determining its role in health and disease.

Lactoferrin (Lf), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of the mammalian innate immune system. Lf’s multiple activities rely not only on its capacity to bind iron, but also to interact with molecular and cellular components of both host and pathogens. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, Lf-bound LPS may retain the capacity to induce cell activation via Toll-like receptor 4-dependent and -independent mechanisms. This review discusses the complex interplay between Lf and LPS and its relevance in the regulation of the immune response.

I saggi che compongono questo libro sono accomunati dall’idea che la poesia ha per Dante un ruolo altissimo in quanto visione di verità assoluta e tramite per un rapporto con l’eternità. Il primo di questi lavori studia appunto la relazione tra verità e visione poetica: relazione che si istituisce al di là della conoscenza comune e attraverso la visione d’amore. Lo studio di Veronica Regoli è volto a cogliere la posizione critica che questa acquisizione dantesca comporta nei confronti della poesia di Guinizzelli, pur nel riconoscimento della sua importanza, e della poesia degli autori che hanno preceduto Dante o che gli sono contemporanei.

Le tre Cariti che tal volta accompagnano Afrodite e le Muse sono figure molto più complesse di quello che sembra in quanto non rivestono un ruolo ancillare per Afrodite stessa o per le Muse: esse hanno una loro dimensione, che possiamo cogliere già in Omero ma che si esplicita chiaramente in Esiodo. Le Cariti sono divinità legate alla danza e ai grandi spazi, ma non sanno soltanto danzare esse possono dare addirittura ad Afrodite qualcosa che a quest'ultima manca e possono specificare le azioni delle Muse. In vari testi possiamo cogliere il carattere della seduzione soprattutto erotica presente in loro, e altrove possiamo vedere in esse specificati attributi dell'eros: la pace con il mondo e con il divino, la sensualità, la finezza del sentimento e della sensibilità (per cui sono importanti per esempio in Saffo). Non si può dunque prescindere, trattando delle Muse e del canto poetico, da queste figure, che donano al canto stesso il potere della seduzione erotica.

Objective In patients with hepatitis C virus (HCV)/HIV co-infection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. Methods Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. Results Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6±0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5±0.3-fold, p=0.03) and gene expression (1.47±0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03±0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-κB (NF-κB) and p38 MAPK . Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. Conclusions This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.

Dendritic cells (DCs) play a key role in the orchestration of the immune system by virtue of their capacity to control both immunity and tolerance induction. The functions of DCs depend on the subset as well as their location and activation state. A number of in vitro protocols, developed to recapitulate DC generation from hematopoietic precursors, have suggested the importance of microenvironment and cytokine milieu in driving the generation of DCs endowed with peculiar phenotypic and functional features. Recently, some important concepts on the development of DCs from human blood monocytes have been challenged. The finding that human DCs can be generated from monocytes in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) alone points to this cytokine as a direct player, rather than a survival-promoting factor, in the development of DCs with distinct properties. This review summarizes the role of different cytokine cocktails in the in vitro generation of human DCs from blood monocyte precursors, focusing on GM-CSF as a direct player in the generation of functionally distinct DCs.