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Alopecia areata is a type of non-scarring hair loss. The dysregulation of numerous systemic Th1 (IL-2, IFN-γ, TNF, IL-12, and IL-18), Th2 (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17E, IL-31 and IL-33) and Th17 (IL-17, IL-17F, IL-21, IL-22, IL-23 and TGF-β) cytokines was observed in patients with alopecia areata. Positive correlations between the severity of alopecia areata and an increased serum level of various cytokines including IL-2, TNF, IL-12, IL-17, and IL-17E were reported in the literature. An increased serum level of numerous cytokines, such as IL-2, IL-6, TNF, IL-12, IL-17E, and IL-22, was described as positively correlated with the duration of the disease. Moreover, it was shown that increased pre-treatment serum level of IL-12 was a positive, while increased serum levels of IL-4 and IL-13 were negative prognostic markers for the efficacy of diphenylcyclopropenone. In conclusion, alopecia areata is associated with the dysregulation of systemic Th1, Th2 and Th17 cytokines with their role in the pathogenesis, clinical manifestations and prognosis of the disease. Available data indicate the most significant role of serum IL-2, TNF, IL-12, IL-17, and IL-17E as markers of disease activity. The serum levels IL-4, IL-12 and IL-13 may be useful as potential predictors of diphenylcyclopropenone efficacy.

Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.

Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.

It remains unknown whether newly identified anti-inflammatory/immunosuppressive cytokine interleukin-35 (IL-35) is different from other anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β in terms of inhibition of inflammation initiation and suppression of full-blown inflammation. Using experimental database mining and statistical analysis methods we developed, we examined the tissue expression profiles and regulatory mechanisms of IL-35 in comparison to other anti-inflammatory cytokines. Our results suggest that in contrast to TGF-β, IL-35 is not constitutively expressed in human tissues but it is inducible in response to inflammatory stimuli. We also provide structural evidence that AU-rich element (ARE) binding proteins and microRNAs target IL-35 subunit transcripts, by which IL-35 may achieve non-constitutive expression status. Furthermore, we propose a new system to categorize anti-inflammatory cytokines into two groups: (1) the house-keeping cytokines, such as TGF-β, inhibit the initiation of inflammation whereas (2) the responsive cytokines including IL-35 suppress inflammation in full-blown stage. Our in-depth analyses of molecular events that regulate the production of IL-35 as well as the new categorization system of anti-inflammatory cytokines are important for the design of new strategies of immune therapies.

The incidence of dengue in Latin America has increased dramatically during the last decade. Understanding the pathogenic mechanisms in dengue is crucial for the identification of biomarkers for the triage of patients. We aimed to characterize the profile of cytokines (IFN-γ, TNF-α, IL-1β, IL-6, IL-18 and IL-10), chemokines (CXCL8/IL-8, CCL2/MCP-1 and CXCL10/IP-10) and coagulation mediators (Fibrinogen, D-dimer, Tissue factor-TF, Tissue factor pathway inhibitor-TFPI and Thrombomodulin) during the dengue-4 epidemic in Brazil. Laboratory-confirmed dengue cases had higher levels of TNF-α (p < 0.001), IL-6 (p = 0.005), IL-10 (p < 0.001), IL-18 (p = 0.001), CXCL8/IL-8 (p < 0.001), CCL2/MCP-1 (p < 0.001), CXCL10/IP-10 (p = 0.001), fibrinogen (p = 0.037), D-dimer (p = 0.01) and TFPI (p = 0.042) and lower levels of TF (p = 0.042) compared to healthy controls. A principal component analysis (PCA) distinguished between two profiles of mediators of inflammation and coagulation: protective (TNF-α, IL-1β and CXCL8/IL-8) and pathological (IL-6, TF and TFPI). Lastly, multivariate logistic regression analysis identified high aspartate aminotransferase-to-platelet ratio index (APRI) as independent risk factors associated with severity (adjusted OR: 1.33; 95% CI 1.03–1.71; p = 0.027), the area under the receiver operating characteristics curve (AUC) was 0.775 (95% CI 0.681–0.869) and an optimal cutoff value was 1.4 (sensitivity: 76%; specificity: 79%), so it could be a useful marker for the triage of patients attending primary care centers.

Biology is meaningful and important to identify cytokines and investigate their various functions and biochemical mechanisms. However, several issues remain, including the large scale of benchmark datasets, serious imbalance of data, and discovery of new gene families. In this paper, we employ the machine learning approach based on a novel ensemble classifier to predict cytokines. We directly selected amino acids sequences as research objects. First, we pretreated the benchmark data accurately. Next, we analyzed the physicochemical properties and distribution of whole amino acids and then extracted a group of 120-dimensional (120D) valid features to represent sequences. Third, in the view of the serious imbalance in benchmark datasets, we utilized a sampling approach based on the synthetic minority oversampling technique algorithm and K-means clustering undersampling algorithm to rebuild the training set. Finally, we built a library for dynamic selection and circulating combination based on clustering (LibD3C) and employed the new training set to realize cytokine classification. Experiments showed that the geometric mean of sensitivity and specificity obtained through our approach is as high as 93.3%, which proves that our approach is effective for identifying cytokines.

Chronic schistosome infections are associated with T-cell hyporesponsiveness and a strong regulatory network. Murine studies have shown that schistosome infections can induce regulatory CD1d(hi) B cells, which inhibit inflammatory responses. Here, we evaluated the influence of regulatory B cells (Bregs) on T-cell cytokines in vitro in human schistosomiasis. Gabonese young adults were recruited from areas where Schistosoma haematobium (S.h) infections were high or low endemic. The study participants were categorized as infected or uninfected from an high endemic area or uninfected from a low endemic (nonendemic) area. Their B cells were studied for Breg subset markers and cocultured with allogenic anti-CD3-stimulated CD4(+) T cells, followed by T-cell cytokine analysis. A greater percentage of B cells from S. haematobium-infected donors expressed cytoplasmic interleukin 10 (IL-10) and membrane-bound latency-associated peptide/transforming growth factor β1, compared with uninfected donors. T cells produced less interferon γ, interleukin 4, and interleukin 17 upon coculture with B cells from schistosome-infected individuals only, while the conversion to CD25(hi)FoxP3(+) and the percentage of IL-10(+) T cells was enhanced. Interestingly, depletion of the prominent IL-10-producing B-cell subset, CD1d(hi) cells, resulted in less IL-10(+) T cells in the S. haematobium-infected group, while levels of FoxP3(+) regulatory T cells remained unaffected. Schistosomes can induce functional Bregs in humans that may be instrumental in general T-cell hyporesponsiveness and may contribute to the increased regulatory milieu found in schistosomiasis.

Primary dysmenorrhea is one of the most common gynecological complaints in young women, but potential peripheral immunologic features underlying this condition remain undefined. In this paper, we compared 84 common cytokine gene expression profiles of peripheral blood mononuclear cells (PBMCs) from six primary dysmenorrheic young women and three unaffected controls on the seventh day before (secretory phase), and the first (menstrual phase) and the fifth (regenerative phase) days of menstruation, using a real-time PCR array assay combined with pattern recognition and gene function annotation methods. Comparisons between dysmenorrhea and normal control groups identified 11 (nine increased and two decreased), 14 (five increased and nine decreased), and 15 (seven increased and eight decreased) genes with ≥ 2-fold difference in expression (P<0.05) in the three phases of menstruation, respectively. In the menstrual phase, genes encoding pro-inflammatory cytokines (IL1B, TNF, IL6, and IL8) were up-regulated, and genes encoding TGF-β superfamily members (BMP4, BMP6, GDF5, GDF11, LEFTY2, NODAL, and MSTN) were down-regulated. Functional annotation revealed an excessive inflammatory response and insufficient TGF-β superfamily member signals with anti-inflammatory consequences, which may directly contribute to menstrual pain. In the secretory and regenerative phases, increased expression of pro-inflammatory cytokines and decreased expression of growth factors were also observed. These factors may be involved in the regulation of decidualization, endometrium breakdown and repair, and indirectly exacerbate primary dysmenorrhea. This first study of cytokine gene expression profiles in PBMCs from young primary dysmenorrheic women demonstrates a shift in the balance between expression patterns of pro-inflammatory cytokines and TGF-β superfamily members across the whole menstrual cycle, underlying the peripheral immunologic features of primary dysmenorrhea.

Outbreaks of infections with viruses like Sars‐CoV‐2, Ebola virus and Zika virus lead to major global health and economic problems because of limited treatment options. Therefore, new antiviral drug candidates are urgently needed. The promising new antiviral drug candidate silvestrol effectively inhibited replication of Corona‐, Ebola‐, Zika‐, Picorna‐, Hepatis E and Chikungunya viruses. Besides a direct impact on pathogens, modulation of the host immune system provides an additional facet to antiviral drug development because suitable immune modulation can boost innate defence mechanisms against the pathogens. In the present study, silvestrol down‐regulated several pro‐ and anti‐inflammatory cytokines (IL‐6, IL‐8, IL‐10, CCL2, CCL18) and increased TNF‐α during differentiation and activation of M1‐macrophages, suggesting that the effects of silvestrol might cancel each other out. However, silvestrol amplified the anti‐inflammatory potential of M2‐macrophages by increasing expression of anti‐inflammatory surface markers CD206, TREM2 and reducing release of pro‐inflammatory IL‐8 and CCL2. The differentiation of dendritic cells in the presence of silvestrol is characterized by down‐regulation of several surface markers and cytokines indicating that differentiation is impaired by silvestrol. In conclusion, silvestrol influences the inflammatory status of immune cells depending on the cell type and activation status.

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell–cell communication, resulting in the deposition of fibrotic and adipose infiltrates. Here, we investigate in vivo changes in the profile of skeletal muscle secretome during the regeneration process to suggest new targetable regulatory circuits whose failure may lead to tissue degeneration in pathological conditions. We describe the kinetic variation of expression levels of 76 secreted proteins during the regeneration process. In addition, we profile the gene expression of immune cells, endothelial cells, satellite cells, and fibro-adipogenic progenitors. This analysis allowed us to annotate each cell-type with the cytokines and receptors they have the potential to synthetize, thus making it possible to draw a cell–cell interaction map. We next selected 12 cytokines whose receptors are expressed in FAPs and tested their ability to modulate FAP adipogenesis and proliferation. We observed that IL1α and IL1β potently inhibit FAP adipogenesis, while EGF and BTC notably promote FAP proliferation. In addition, we characterized the cross-talk mediated by extracellular vesicles (EVs). We first monitored the modulation of muscle EV cargo during tissue regeneration. Using a single-vesicle flow cytometry approach, we observed that EVs differentially affect the uptake of RNA and proteins into their lumen. We also investigated the EV capability to interact with SCs and FAPs and to modulate their proliferation and differentiation. We conclude that both cytokines and EVs secreted during muscle regeneration have the potential to modulate adipogenic differentiation of FAPs. The results of our approach provide a system-wide picture of mechanisms that control cell fate during the regeneration process in the muscle niche.