Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Systematic profiling and identification of the peptide-mediated interactions between human Yes-associated protein and its partners in esophageal cancer.

Human Yes-associated protein (YAP) is involved in the Hippo signaling pathway and serves as a coactivator to modulate gene expression, which contains a transactivation domain (TD) responsible for binding to the downstream TEA domain family (TEAD) of transcription factors and two WW1/2 domains that recognize the proline-rich motifs (PRMs) present in a variety of upstream protein partners through peptide-mediated interactions (PMIs). The downstream YAP TD-TEAD interactions are closely associated with gastric cancer, and a number of therapeutic agents have been developed to target the interactions. In contrast, the upstream YAP WW1/2-partner interactions are thought to be involved in esophageal cancer but still remain largely unexplored. Here, we attempted to elucidate the complicated PMIs between the YAP WW1/2 domains and various PRMs of YAP-interacting proteins. A total of 106 peptide segments carrying the class I WW-binding motif [P/L]Px[Y/P] were extracted from 22 partner candidates, which are potential recognition sites of YAP WW1/2 domains. Structural and energetic analyses of the intermolecular interactions between the domains and peptides created a systematic domain-peptide binding profile, from which a number of biologically functional PMIs were identified and then substantiated in vitro using fluorescence spectroscopy assays. It is revealed that: (a) The sequence requirement for the partner recognition site binding to YAP WW1/2 domains is a decapeptide segment that contains a core PRM motif as well as two three-residue extensions from each side of the motif; the core motif and extended sections are responsible for the binding stability and recognition specificity of domain-peptide interaction, respectively. (b) There is an exquisite difference in the recognition specificity of the two domains; the LPxP and PPxP appear to more prefer WW1 than WW2, whereas the WW2 can bind more effectively to LPxY and PPxY than WW1. (c) WW2 generally exhibits a higher affinity to the panel of recognition site candidates than WW1. In addition, a number of partner peptides were found as promising recognition sites of the two domains and/or to have a good selectivity between the two domains. For example, the DVL1 peptide was determined to have moderate affinity to WW2 and strong selectivity for WW2 over WW1. Hydrogen bonds play a central role in selectivity.

Design, synthesis and evaluation of 2-(2-oxoethyl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors.

A novel series of 2-(2- oxoethyl)pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that compound 10q showed the best inhibitory activity against AChE (IC50 = 0.88 ± 0.78 µM), which was better than that of Huperzine-A, and its inhibitory effect on BuChE was weak (IC50 = 10.0 ± 1.30 µM), which indicated that compound 10q was a dominant AChE inhibitor. In addition, the result of molecular docking study displayed that 10q could simultaneously bind to CAS and PAS sites of AChE, which was consistent with the mixed inhibition mode shown by the enzymatic kinetics study of 10q. Furthermore, the molecular properties of the target compounds were predicted online using the molinspiration server and pkCSM, The results exhibited that compound 10q had drug-like properties that satisfied the Lipinski's rule of five. Based on the bioactivity and molecular properties, compound 10q for further development was valuable.

High expression of eIF4A1 predicts unfavorable prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a worldwide malignancy with high morbidity and mortality. Translation initiation factor 4A1 (eIF4A1), which is an ATP-dependent RNA helicase as a part of eIF4F complex, has been linked to malignant transformation and progression, and a variety of cancers display dysregulation of this enzyme. However, its role in ccRCC remains unclear. In our study, we examined its potential effects in ccRCC. METHODS: Based on Proteomic data, TCGA and ONCOMINE database, RCC cell lines and tissues, the expression of eIF4A1 between ccRCC and normal tissues were investigated. A correlation was evaluated between the prognostic model for OS and ccRCC progression. Analysis of functional enrichment and PPI network were performed. After examining differentially expressed genes between the eIF4A1 high and low-expression groups, we performed GSEA analysis. Furthermore, we investigated immune cell infiltration of eIF4A1. Then we determined eIF4A1 functions in the establishment and maintenance of cell viability, migration and invasion of cell lines. Flow cytometry was utilized to detect cell cycle. RESULTS: The eIF4A1 was up-regulated in ccRCC tissues and cell lines. An increased level of eIF4A1 was linked to lower survival rates and impaired immunity. Depletion of eIF4A1 could arrest tumor cells in G1 phase, so as to seriously limit cell proliferation and weaken the capacity of cell migration. CONCLUSION: ccRCC patients with high eIF4A1 expression are at increased risk of poor prognosis, furthermore eIF4A1 plays a prominent role in facilitating tumor cell proliferation and migration which may further be a potential prognostic biomarker and therapeutic target.

Sleep duration and efficiency are associated with plasma amyloid-ß in non-demented older people.

STUDY OBJECTIVES: This study aims to investigate the extent to which sleep duration and efficiency are associated with plasma amyloid-ß (Aß) levels in non-demented older people. METHODS: This study is a cross-sectional analysis of 305 non-demented older people. Sleep duration and efficiency were assessed used the Pittsburgh Sleep Quality Index. Levels of plasma Aß were determined by sandwich enzyme-linked immunosorbent assay technique. Associations between sleep variables and plasma Aß levels were evaluated with multivariable linear regression analysis. RESULTS: Compared to those with sleep duration > 7 h, participants with sleep duration < 6 h had a higher plasma Aß42 level (ß = 0.495, 95% CI 0.077~0.913, p = 0.021) and Aß42/Aß40 ratio (ß = 0.101, 95% CI 0.058~0.144, p < 0.001). Compared to those with sleep efficiency ≥ 85%, participants with lower sleep efficiency (65~74%, <65%) had a higher level of plasma Aß42 (<65%: ß = 0.627, 95% CI 0.147~1.108, p = 0.011) and Aß42/Aß40 ratio (65~74%: ß = 0.052, 95% CI 0.007~0.097, p = 0.026; <65%: ß = 0.117, 95% CI 0.067~0.168, p < 0.001). CONCLUSIONS: These findings indicated that short sleep duration and low sleep efficiency were associated with a high level of Aß42. A better comprehending of the link between sleep and plasma Aß levels may lead to effective sleep-based intervention to reduce the risk of Alzheimer's disease.

Lipin1 mediates cognitive impairment in fld mice via PKD-ERK pathway.

Lipin1 is important in lipid synthesis because of its phosphatidate phosphatase activity, and it also functions as transcriptional coactivators to regulate the expression of genes involved in lipid metabolism. We found that fld mice exhibit cognitive impairment, and it is related to the DAG-PKD-ERK pathway. We used fld mice to explore the relationship between lipin1 and cognitive function. Our results confirmed the presence of cognitive impairment in the hippocampus of lipin1-deficient mice. As shown in behavioral test, the spatial learning and memory ability of fld mice was much worse than that of wild-type mice. Electron microscopy results showed that the number of synapses in hippocampus of fld mice was significantly reduced. BDNF,SYP, PSD95 were significantly reduced. These results suggest that lipin1 impairs synaptic plasticity. Hence,a deficiency of lipin1 leads to decreased DAG levels and inhibits PKD activation, thereby affecting the phosphorylation of ERK and the CREB.

Overexpression of Siah2 Is Associated With Poor Prognosis in Patients With Epithelial Ovarian Carcinoma.

OBJECTIVES: Seven in absentia homolog 2 (Siah2) is an E3 ubiquitin ligase that is expressed in mammals and is homologous to seven in absentia in Drosophila. Siah2 is involved in the progression of many malignancies. However, the role of Siah2 in ovarian cancer remains unclear. This study aims to evaluate the prognostic value of Siah2 expression for epithelial ovarian carcinoma (EOC) patients. MATERIALS AND METHODS: Immunohistochemical analysis was conducted using 32 normal ovarian specimens and 122 ovarian carcinoma specimens, respectively. We analyzed the correlations of Siah2 expression with the clinicopathological factors and prognosis of ovarian cancer patients. χ Analysis, Kaplan-Meier method, and multivariate Cox proportional hazard analysis were conducted for statistical analyses. RESULTS: Immunohistochemical staining demonstrated that the expression of Siah2 was higher in the EOC tissues than in the normal tissues. High Siah2 expression positively correlated with histological grade and lymph node metastasis but not with age, histologic type, International Federation of Gynecology and Obstetrics staging, and CA125. Patients with positive Siah2 expression showed lower overall survival and disease-free survival rates than those with negative Siah2 expression (P < 0.05 for both). Multivariate Cox analysis indicated that Siah2 was an independent parameter for overall survival (hazards ratio, 2.166; 95% confidence interval, 1.182-3.970; P = 0.012) and disease-free survival (hazards ratio, 1.819; 95% confidence interval, 1.030-3.216; P = 0.039). CONCLUSIONS: Siah2 is possibly involved in tumor development and progression in EOC. Thus, Siah2 is a promising biomarker for predicting the prognosis of ovarian cancer patients and may serve as a novel target for treating ovarian carcinoma.

Overexpression of ANCCA/ATAD2 in endometrial carcinoma and its correlation with tumor progression and poor prognosis.

This study aimed to explore the clinical significance of AAA+ (ATPases associated with various cellular activities) nuclear coregulator cancer-associated (ANCCA) protein expression in endometrial carcinoma (EC). Correlations of ANCCA expression with clinicopathological factors and prognosis of EC patients were analyzed. Expression of ANCCA was detected in EC from 207 patients along with corresponding normal endometrium specimens by immunohistochemistry. ANCCA immunoreactivity was overexpressed in EC cases compared with that in normal endometrium (P < 0.001). High ANCCA expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, depth of myometrial invasion, lymph node metastasis, lymph vascular space involvement, and recurrence but not with age and histological type. Patients with high ANCCA expression exhibited significantly poorer overall survival (OS) and disease-free survival (DFS) than patients with low ANCCA expression (P = 0.001 and 0.002, respectively). Cox multivariate analysis showed that high ANCCA expression was an independent prognostic factor for both OS (hazard ratio (HR) = 4.954, 95 % confidence interval (CI) = 1.537-15.966; P = 0.007) and DFS of patients with EC (HR = 4.237, 95 % CI = 1.295-13.859; P = 0.017). We identified ANCCA protein expression as a novel independent poor prognostic indicator in EC.

Special AT-rich sequence-binding protein 1: a novel biomarker predicting cervical squamous cell carcinoma prognosis and lymph node metastasis.

OBJECTIVE: Special AT-rich sequence-binding protein 1 is aberrantly expressed in various malignant tumors. However, the expression and function of special AT-rich sequence-binding protein 1 in cervical squamous cell carcinoma have not been reported. The objective of this study was to investigate the clinical significance of special AT-rich sequence-binding protein 1 in cervical squamous cell carcinoma. METHODS: In this study, we investigated the expression of special AT-rich sequence-binding protein 1 through immunohistochemistry in 25 normal cervix specimens and 167 cervical squamous cell carcinomas and analyzed its association with various clinicopathologic parameters, including patient outcome. RESULTS: Special AT-rich sequence-binding protein 1 protein was detected in 58 (34.7%) out of 167 patients and was highly related to International Federation of Gynecology and Obstetrics stage, histologic grade, lymph node metastasis, vascular-lymphatic invasion and recurrence of cervical squamous cell carcinoma. Patients with positive special AT-rich sequence-binding protein 1 expression had significantly lower overall survival and disease-free survival compared with patients with negative expression of special AT-rich sequence-binding protein 1 (P = 0.001 and P < 0.001, respectively). A multivariate Cox regression analysis revealed that special AT-rich sequence-binding protein 1 was an independent prognostic marker for both disease-free survival and overall survival of cervical squamous cell carcinoma patients (P = 0.038 and P = 0.010, respectively). A multivariate logistic regression analysis showed that special AT-rich sequence-binding protein 1 expression was strongly associated with lymph node metastasis (odds ratio = 2.497; P = 0.032). Sensitivity and specificity of special AT-rich sequence-binding protein 1 for lymph node metastasis were 61.0 and 73.8%, respectively. CONCLUSIONS: These results showed that special AT-rich sequence-binding protein 1 expression was associated with tumor progression, metastasis and poor prognosis in cervical squamous cell carcinoma. It may serve as a new prognostic biomarker or a target for improving the treatment efficiency of patients with cervical squamous cell carcinoma.

Overexpression of special AT-rich sequence-binding protein 1 in endometrial cancer: a clinicopathologic study.

OBJECTIVE: Special AT-rich sequence-binding protein 1 (SATB1), as a genome organizer, serves important functions in tumor progression and metastasis. The SATB1 is overexpressed in various malignant tumors. However, the expression and prognostic value of SATB1 in endometrial cancer remain unknown. The aim of this study was to explore the prognostic values of SATB1 expression in endometrial cancer. METHODS/MATERIALS: We investigated the expression of SATB1 in 172 untreated endometrial cancer tissues and 25 normal endometrial tissues through immunohistochemical staining. We also analyzed the association of SATB1 level with clinicopathologic parameters and determined its prognostic significance. RESULT: Special AT-rich sequence-binding protein 1 was expressed in 78 (45.3%) of the 172 endometrial cancer samples, but not in the normal endometrial samples. The positive expression of SATB1 was associated with clinicopathologic factors, such as International Federation of Gynecology and Obstetrics stage, histological grade, myometrial invasion depth, lymph node metastasis, vascular/lymphatic invasion, and recurrence. The patients with positive SATB1 expression had worse overall survival and disease-free survival rates than the patients with negative SATB1 expression (P < 0.001 for both). Multivariate Cox analysis indicated that SATB1 was an independent parameter for overall survival (hazards ratio, 2.928; 95% confidence interval, 1.072-7.994; P = 0.036) and disease-free survival (hazards ratio, 2.825; 95% confidence interval, 1.111-7.181; P = 0.029). CONCLUSIONS: Results showed that SATB1 may be involved in tumor development and progression in endometrial cancer, may serve as a promising biomarker for predicting the prognosis of endometrial cancer patients, and thus may act as a novel target for treating endometrial carcinoma.

Preoperative neutrophil-lymphocyte ratio before platelet-lymphocyte ratio predicts clinical outcome in patients with cervical cancer treated with initial radical surgery.

OBJECTIVE: Several inflammatory parameters are applied to predict the survival of patients with various cancers. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are 2 nonspecific markers of systemic inflammation. This study aimed to evaluate the clinicopathologic and prognostic values of NLR and PLR in patients with cervical cancer undergoing primary radical hysterectomy with pelvic lymphadenectomy. METHODS: A total of 460 cervical cancer patients were enrolled in this study. These patients were histologically confirmed with cervical cancer from February 2005 to June 2008, at the Department of Gynecology, the Third Affiliated Hospital of Harbin Medical University, China. Their clinical and histopathological markers and complete blood counts were collected and analyzed. Prognostic factors were assessed by univariate and multivariate analyses. RESULTS: The median NLR and PLR were 2.213 and 150.9, respectively. The clinicopathologic analysis showed that NLR was highly associated with depth of stromal infiltration (P = 0.007) and lymph node metastasis (P = 0.003), and PLR was significantly related to tumor size (P = 0.020) and lymph node metastasis (P = 0.027).Univariate analysis identified high NLR as a statistically significant poor predictive factor for the progression-free survival (PFS) (P = 0.008) and overall survival (OS) (P = 0.014), and PLR exhibited no significance on PFS (P = 0.075) and OS (P = 0.110).Multivariable analysis showed that the NLR was an independent prognostic marker for PFS (hazard ratio, 1.799; 95% confidence interval, 1.069-3.028; P = 0.027), but not for OS (hazard ratio, 1.631; 95% confidence interval, 0.968-2.750; P = 0.066). CONCLUSIONS: Preoperative NLR and PLR were found to be correlated to unfavorable histopathologic features of cervical cancer. The preoperative NLR, but not PLR, may be used as a potential and easy biomarker for survival prognosis in patients with cervical cancer receiving initial radical hysterectomy with pelvic lymphadenectomy.

Melamine-induced urinary calculi in infants--sonographic manifestations and outcomes 1 year after exposure.

BACKGROUND: In 2008, the melamine-tainted-milk incident started with reports of increased incidence of urolithiasis in infants in China. Affected children were screened for urolithiasis. OBJECTIVE: The purpose of this study was to analyze sonographic characterization of infant melamine-induced urolithiasis. MATERIALS AND METHODS: Transabdominal US examination was done in 603 infants with melamine-induced calculi. The imaging characteristics of calculi and hydronephrosis were analyzed. Follow-up US imaging was performed. RESULTS: Comet-tail sign was seen behind the calculus of <4 mm. Calculi of ≥ 4 mm were found in 299 inpatients with clear posterior border and with or without light shadowing. Solitary and multiple stones had similar incidence. Incidence of calculi in the inferior renal calyx was the highest (55.2%) in inpatients. Calculus size in inpatients age 2-3 years was smaller than that of children younger than 2 years old (P < 0.05). Inpatients age 2-3 years had the highest incidence rate (48.0%) of hydronephrosis. CONCLUSION: Calculi of <4 mm manifested as hyperechoic foci near the renal papillae, while calculi of ≥ 4 mm usually manifested as echogenic foci with visible inferior edge in the renal calyx. Hydronephrosis was a common imaging finding in inpatients ages 2-3 years.

Microstructural study on Kirkendall void formation in Sn-containing/Cu solder joints during solid-state aging.

Kirkendall void formation at the solder/metallization interface is an important reliability concern for Cu conductors and under-bump metallization in microelectronic packaging industry, whose mechanism is still hard to be understood for different individual cases. In the present work, two typical solder/Cu-diffusing couples, eutectic SnIn/Cu and SnBi/Cu, were studied by scanning/transmission electron microscopy to investigate the microstructural evolution and voiding process after soldering and then solid-state aging. It was concluded that Kirkendall voids formed between two sublayers within Cu2(In,Sn) phase in eutectic SnIn/Cu solder joint, whereas they appeared at the Cu3Sn/Cu interface or within Cu3Sn for eutectic SnBi/Cu solder joint. Besides the effect of impurity elements, the morphological difference within one intermetallic compound layer could change the diffusing rates of reactive species, hence resulting in void formation in the reaction zone.

Emerging roles of olfactory receptors in glucose metabolism.

Olfactory receptors (ORs) are widely expressed in extra-nasal tissues, where they participate in the regulation of divergent physiological processes. An increasing body of evidence over the past decade has revealed important regulatory roles for extra-nasal ORs in glucose metabolism. Recently, nonodorant endogenous ligands of ORs with metabolic significance have been identified, implying the therapeutic potential of ORs in the treatment of metabolic diseases, such as diabetes and obesity. In this review, we summarize current understanding of the expression patterns and functions of ORs in key tissues involved in glucose metabolism modulation, describe odorant and endogenous OR ligands, explain the biased signaling downstream of ORs, and outline OR therapeutic potential.

The complete mitochondrial genome of a new species of the genus Schizothorax from Sichuan, China (Cypriniformes: Cyprinidae).

Schizothorax gulinensis sp. nov. is a new species of the genus Schizothorax from Sichuan, China (Cypriniformes: Cyprinidae). In this study, we have first reported the complete mitochondrial genome of S. gulinensis with Illumina sequencing. There were 16,587 nucleotide pairs in the mitochondrial genome (mitogenome) of S. gulinensis, including 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs), as well as one non-coding control region (CR). The proportion of nucleotides in mitochondrial genome was 29.67% (A), 25.45% (T), 17.84% (G), 27.05% (C), and A + T content was 55.12%. All PCGs have the same start codon of the standard ATG, excepting for that of NADH dehydrogenase subunit 1 (nad1) which was the ATC, NADH dehydrogenase subunit 5 (nad5) which was the ATT and cytochrome c oxidase 1 (cox1) which was the ATC. Phylogenetic analysis results supported that S. gulinensis was closely related to Schizothorax grahami. The complete mitochondrial sequence of S. gulinensis will contribute to mitochondrial genome database and provide useful resources for population genetics and evolution analyses.

Brain Activation During Working Memory Task in Amnestic Mild Cognitive Impairment Patients and Its Association with Memory and Attention.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is regarded as a transitional state of Alzheimer's disease, with working memory (WM) impairment. OBJECTIVE: To investigate the brain activity in aMCI patients during WM tasks with the functional near-infrared spectroscopy (fNIRS) technique, as well as explore the association between brain activity and cognitive function in multiple domains. METHODS: This study is a case-control study of 54 aMCI patients and 33 cognitively healthy elderly (NC). All participants underwent neuropsychological assessments. fNIRS was applied to examine the brain activation during the WM task. Multivariable linear regression analysis was applied to evaluate associations between brain activation and cognitive function in multiple domains. RESULTS: Compared to NC subjects, aMCI patients had lower activation in the bilateral prefrontal, parietal, and occipital cortex during the WM task. Additionally, activation in the left prefrontal, bilateral parietal, and occipital cortex during the encoding and maintenance phase was positively associated with memory function. During memory retrieval, higher activity in the left prefrontal, parietal, and occipital cortex were correlated with higher memory scores. Besides, a positive association also formed between attention function and the activation in the left prefrontal, parietal, and occipital cortex during the WM task. CONCLUSION: These findings demonstrated that reduced activation in the prefrontal, parietal and occipital cortex during WM might reflect the risk of cognitive impairment, especially memory and attention function in aMCI patients. Given the brain activation visualization, fNIRS may be a convenient and alternative tool for screening the risk of Alzheimer's disease.

Unsaturated bond recognition leads to biased signal in a fatty acid receptor.

Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.

l1-Norm Quantile Regression Screening Rule via the Dual Circumscribed Sphere.

l1-norm quantile regression is a common choice if there exists outlier or heavy-tailed error in high-dimensional data sets. However, it is computationally expensive to solve this problem when the feature size of data is ultra high. As far as we know, existing screening rules can not speed up the computation of the l1-norm quantile regression, which dues to the non-differentiability of the quantile function/pinball loss. In this paper, we introduce the dual circumscribed sphere technique and propose a novel l1-norm quantile regression screening rule. Our rule is expressed as the closed-form function of given data and eliminates inactive features with a low computational cost. Numerical experiments on some simulation and real data sets show that this screening rule can be used to eliminate almost all inactive features. Moreover, this rule can help to reduce up to 23 times of computational time, compared with the computation without our screening rule.

Role of IL-6 in dendritic cell functions.

Dendritic cells (DCs) are efficient antigen-presenting cells that serve as a link between the innate and adaptive immune systems. These cells are broadly involved in cellular and humoral immune responses by presenting antigens to initiate T cell reactions, cytokine and chemokine secretion, T cell differentiation and expansion, B cell activation and regulation, and the mediation of immune tolerance. The functions of DCs depend on their activation status, which is defined by the stages of maturation, phenotype differentiation, and migration ability, among other factors. IL-6 is a soluble mediator mainly produced by a variety of immune cells, including DCs, that exerts pleiotropic effects on immune and inflammatory responses through interaction with specific receptors expressed on the surface of target cells. Here, we review the role of IL-6, when generated in an inflammatory context or as derived from DCs, in modulating the biologic function and activation status of DCs and emphasize the importance of searching for novel strategies to target the IL-6/IL-6 signaling pathway as a means to diminish the inflammatory activity of DCs in immune response or to prime the immunogenic activity of DCs in immunosuppressive conditions.