Regulated Upon Activation Normal T Cell Expressed And Secreted Research Articles

Potential role of IGF-1R in the interaction between orbital fibroblasts and B lymphocytes: an implication for B lymphocyte depletion in the active inflammatory phase of thyroid-associated ophthalmopathy

BackgroundThyroid eye disease (TED) is an inflammatory process involving lymphocyte-mediated immune response and orbital tissue damage. The anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies produced by B lymphocytes are involved in the activation of orbital fibroblasts and the inflammatory process of orbital tissue damage in TED. The purpose of this study was to explore the role of IGF-1R in the mechanistic connection between orbital fibroblasts and B lymphocytes in TED.MethodsOrbital fibroblasts sampled from orbital connective tissues and peripheral B lymphocytes isolated from peripheral blood, which were obtained from 15 patients with TED and 15 control patients, were co-cultured at a ratio of 1:20. The level of IGF-1R expression in orbital fibroblasts was evaluated by flow cytometry and confocal microscopy. Transient B lymphocyte depletion was induced with anti-CD20 monoclonal antibody rituximab, while the IGF-1R pathway was blocked by the IGF-1R binding protein. The expression levels of interleukin-6 (IL-6) and regulated upon activation, normal T cell expressed and secreted (RANTES) in the co-culture model were quantified via ELISA.ResultsIGF-1R expression was significantly elevated in TED orbital fibroblasts compared to that of controls. A 24-h co-culture of orbital fibroblasts with peripheral B lymphocytes induced elevated expression levels of IL-6 and RANTES in each group (TED patients and controls), with the highest levels occurring in TED patients (T + T group). Rituximab and IGF-1R binding protein significantly inhibited increased levels of IL-6 and RANTES in the co-culture model of TED patients.ConclusionsIGF-1R may mediate interaction between orbital fibroblasts and peripheral B lymphocytes; thus, blocking IGF-1R may reduce the local inflammatory response in TED. Rituximab-mediated B lymphocyte depletion played a role in inhibiting inflammatory responses in this in vitro co-culture model, providing a theoretical basis for the clinical application of anti-CD20 monoclonal antibodies in TED.

Novel biomarkers in patients with uncontrolled hypertension with and without kidney damage

Introduction Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR) are insensitive biomarkers for early detection of hypertension-mediated organ damage (HMOD). In this nationwide cross-sectional study, we assessed potential biomarkers for early HMOD in healthy persons and patients with hypertension. We hypothesised that plasma levels of biomarkers: (1) are different between healthy controls and patients with hypertension, (2): can classify patients with hypertension according to the degree of hypertension severity. Design and methods Patients with hypertension prescribed ≥2 antihypertensive agents were selected from a multicentre study. Healthy controls were selected from an ongoing study of living kidney donor candidates. Uncontrolled hypertension was defined as systolic daytime ambulatory blood pressure ≥135 mmHg. Kidney HMOD was defined by ACR > 3.0 mg/mmol or eGFR < 60 mL/min/1.73 m2. Patients with hypertension were categorised into three groups: (1) controlled hypertension; (2) uncontrolled hypertension without kidney HMOD; (3) uncontrolled hypertension with kidney HMOD. Fifteen biomarkers were analysed using a Luminex bead-based immunoassay, and nine fell within the specified analytical range. Results Plasma levels of Interleukin 1 receptor antagonist (IL-1RA), neutrophil gelatinase-associated lipocalin (NGAL) and uromodulin were significantly different between healthy controls (n = 39) and patients with hypertension (n = 176). In regression models, with controlled hypertension (n = 55) as the reference category, none of the biomarkers were associated with uncontrolled hypertension without (n = 59) and with (n = 62) kidney HMOD. In models adjusted for cardiovascular risk factors and eGFR, osteopontin (OPN) was associated with uncontrolled hypertension without kidney HMOD (odds ratio (OR) 1.77 (1.05–2.98), p = 0.03), and regulated upon activation normal T-cell expressed and secreted (RANTES) with uncontrolled hypertension with kidney HMOD (OR 0.57 (0.34–0.95), p = 0.03). Conclusions None of the biomarkers could differentiate our hypertension groups when established risk factors were considered. Plasma OPN may identify patients with uncontrolled hypertension at risk for kidney HMOD.

Association Between Cervical Inflammatory Mediators and Prevalent Cervical Human Papillomavirus Infection.

Inflammatory mediators are important regulators of immune response and can modulate the inflammation caused by viral infections, including human papillomavirus (HPV). In this study, we evaluated the association between cervical immune mediators, including chemokines, cytokines, and growth factors with HPV infections. We used a nonmagnetic bead-based multiplex assay to determine 27 immune mediators in cervical secretions collected from 275 women in a prospective longitudinal cohort design. All the study participants were age 18 years or older, had a history of vaginal sexual intercourse, were not currently pregnant, and had no history of cervical disease or hysterectomy. The mean (±standard deviation) age of the participants was 41 (±8) years, and about half (51% [141/275]) were HPV-positive, of whom 7% (10/141) had low-risk HPV (lrHPV), 61% (86/141) had high-risk HPV (hrHPV), and 32% (45/141) had both lrHPV and hrHPV infections. Higher concentrations of some immune mediators were associated with HPV infections, including eotaxin, interferon-gamma, interleukin (IL)-1β, IL-2, IL-4, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated upon activation normal T-cell expressed and secreted (RANTES), and tumor necrosis factor (TNF)-α and any HPV; IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p70, and IL-13 and lrHPV; and eotaxin, interferon, IL-1B, IL-4, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, MIP-1α, MIP-1β, RANTES, TNF-α concentrations, and hrHPV infections. Higher concentrations of granulocyte macrophage colony-stimulating factor, IL-1 receptor antagonist (IL-1Ra), and monocyte chemotactic protein-1 (MCP-1) were associated with reduced odds of any HPV, while IL-1Ra and MCP-1 were associated with reduced odds of hrHPV infections. Several chemokines, cytokines, and growth factors are associated with group-specific HPV infections in this population of women. These important findings contribute to the understanding of the immune response to HPV, cytokine profiles and their potential implications for cervical pathogenesis, and can guide future research in this field.

Leaves and pseudostems extract of Curcuma longa attenuates immunoglobulin E/bovine serum albumin-stimulated bone marrow-derived cultured mast cell activation and passive cutaneous anaphylaxis in BALB/c mice

Ethnopharmacological relevanceCurcuma longa, known as turmeric, is an herbaceous perennial plant belonging to the genus Curcuma. It is dispersed throughout tropical and subtropical regions worldwide. Since ancient times, turmeric has been used as an ethnomedicinal plant in the Ayurvedic system, particularly in Asian countries. Rhizomes of turmeric possess several pharmacological properties that give high value as a medicinal remedy for treating a range of conditions, including inflammation, pain, allergies, and digestive issues. Moreover, turmeric leaves and pseudostems also contain a variety of health-enhancing secondary metabolites, such as curcumin, flavonoids, and other phenolic compounds, which exhibit anti-inflammatory, antitumor, antibacterial, and antioxidant properties. Aim of the studyAllergic diseases are a group of immune-mediated disorders mainly caused by an immunoglobulin E (IgE)-dependent immunological response to an innocuous allergen. Therefore, this study aimed to investigate the effect of leaves and pseudostems extract of turmeric (TLSWE-8510) on IgE/bovine serum albumin (BSA)-stimulated allergic responses in mouse bone marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in BALB/c mice. Materials and methodsThe effect of TLSWE-8510 on mast cell degranulation has been evaluated by investigating the release of β-hexosaminidase and histamine in IgE/BSA-stimulated BMCMCs. Additionally, anti-allergic properties of TLSWE-8510 on IgE/BSA-stimulated BMCMCs were investigated using suppression of nuclear factor-kappa B (NF-κB), and spleen tyrosine kinase (Syk)-linker for T-cell activation (LAT)-extracellular-signal-regulated kinase (ERK)-GRB2 associated binding protein 2 (Gab2) signaling pathway and downregulation of allergy-related cytokines and chemokines expression. Furthermore, in vivo, studies were conducted using IgE-mediated PCA in BALB/c mice. ResultsTLSWE-8510 treatment significantly inhibited the degranulation of IgE/BSA-stimulated BMCMCs by inhibiting the release of β-hexosaminidase and histamine dose-dependently. Additionally, TLSWE-8510 reduced the expression of high-affinity IgE receptors (Fc epsilon receptor I-FcεRI) on the surface of BMCMCs and the binding of IgE to FcεRI. Besides, the expression of cytokines and chemokines is triggered by IgE/BSA stimulation via activating the allergy-related signaling pathways. TLSWE-8510 dose-dependently downregulated the mRNA expression and the production of allergy-related cytokines (interleukin (IL)-1β, IL-3, IL-4, IL-5, IL-6, IL-13, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ), and chemokines (thymus and activation-regulated chemokine (TARC), and regulated upon activation, normal T cell expressed and secreted (RANTES)) by regulating the phosphorylation of downstream signaling molecules, NF-κB, and Syk, LAT, ERK and Gab2 in IgE/BSA-stimulated BMCMCs. Moreover, PCA reaction in IgE/BSA-stimulated BALB/c mice ears was effectively decreased by TLSWE-8510 treatment in a dose-dependent manner. ConclusionsThese results collectively demonstrated that TLSWE-8510 suppressed mast cell degranulation by inhibiting the release of chemical mediators related to allergies. TLSWE-8510 downregulated the allergy-related cytokines and chemokines expression and phosphorylation of downstream signaling molecules in IgE/BSA-stimulated BMCMCs. Furthermore, in vivo studies with IgE-mediated PCA reaction in the BALB/c mice ears were attenuated by TLSWE-8510 treatment. These findings revealed that TLSWE-8510 has the potential as a therapeutic agent for the treatment of allergic diseases.

Genetically predicted circulating levels of cytokines and the risk of depression: a bidirectional Mendelian-randomization study.

Objective: Inflammatory cytokines disturbance is the main result of immune dysregulation, which is widely described in major depressive disorder (MDD). However, the potential causal relationship between these two factors has not been discovered. Therefore, the purpose of this study was to investigate the causal relationship between inflammatory cytokines and MDD risk by using the two-sample Mendelian randomization (MR) analysis. Method: Two genetic instruments obtained from publicly available gene profile data were utilized for the analysis. We obtained the genetic variation data of 41 inflammatory cytokines from genome-wide association studies (GWAS) meta-analysis of 8293 individuals of Finnish descent. The MDD data, including 135,458 MDD cases and 344,901 controls, were obtained from the Psychiatric Genomics Consortium Database. For the Mendelian randomization (MR) estimation, several methods were employed, namely, MR-Egger regression, inverse-variance weighted (IVW), weighted median, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Result: A causal relationship was identified between the genetically proxied levels of Interleukin (IL) -18, IL-1β, and Regulated upon activation normal T cell expressed and secreted (RANTES) and the risk of MDD (OR = 0.968, 95%CI = 0.938, 0.998, p = 0.036; OR = 0.875, 95%CI = 0.787, 0.971, p = 0.012; OR = 0.947, 95%CI = 0.902, 0.995, p = 0.03; respectively). However, our Mendelian randomization (MR) estimates provided no causality of MDD on inflammatory cytokines. Conclusion: Our study elucidates the connection between inflammatory cytokines and MDD by using MR analysis, thereby enhancing our comprehension of the potential mechanisms. By identifying these associations, our findings hold substantial implications for the development of more effective treatments aimed at improving patient outcomes. However, further investigation is required to fully comprehend the exact biological mechanisms involved.

Anti-Atopic Effect of Isatidis Folium Water Extract in TNF-α/IFN-γ-Induced HaCaT Cells and DNCB-Induced Atopic Dermatitis Mouse Model.

Isatidis folium or Isatis tinctoria L. is a flowering plant of the Brassicaceae family, commonly known as woad, with an ancient and well-documented history as an indigo dye and medicinal plant. This study aimed to evaluate the anti-atopic dermatitis (AD) effects of Isatidis folium water extract (WIF) using a 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse model and to investigate the underlying mechanism using tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-activated HaCaT cells. Oral administration of WIF reduced spleen weight, decreased serum IgE and TNF-α levels, reduced epidermal and dermal thickness, and inhibited eosinophil and mast cell recruitment to the dermis compared to DNCB-induced control groups. Furthermore, oral WIF administration suppressed extracellular signal-regulated kinase and p38 mitogen-activated protein kinase protein expression levels, p65 translocation from the cytoplasm to the nucleus, and mRNA expression of TNF-α, IFN-γ, interleukin (IL)-6, and IL-13 in skin lesion tissues. In HaCaT cells, WIF suppressed the production of regulated upon activation, normal T cell expressed and secreted (RANTES), thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), MCP-1, and MIP-3a, which are inflammatory cytokines and chemokines related to AD, and inhibited the mRNA expression of RANTES, TARC, and MDC in TNF-α/IFN-γ-stimulated HaCaT cells. Overall, the results revealed that WIF ameliorated AD-like skin inflammation by suppressing proinflammatory cytokine and chemokine production via nuclear factor-κB pathway inhibition, suggesting WIF as a potential candidate for AD treatment.

RANTES (CCL5) in Patients With Geographic Atrophy Age-Related Macular Degeneration.

A previous study from our research group showed significantly lower levels of RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in patients with intermediate age-related macular degeneration (AMD) compared to control patients with no AMD. The primary aim of this study was to assess levels of RANTES in a cohort of patients with a more advanced form of the disease, geographic atrophy (GA), in comparison with controls. The study was conducted on a cohort of patients with GA recruited into a Colorado AMD registry. Cases and controls were defined with multimodal imaging. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction. The plasma levels of RANTES were significantly higher in the control group in comparison to the GA AMD group (median [interquartile range]): 10,204 [5799-19,554] pg/mL vs. 5435 [3420-9177] pg/mL, respectively, P < 0.01). When moderated by sex, there was no statistical difference between the male and female GA AMD or the male and female controls. We found lower level of RANTES in patients with GA AMD compared with controls. This finding is consistent with the findings from our previous intermediate AMD study. However, in contrast to the results of our previous research, when moderated by sex there was no statistical difference between male and female GA patients. The biomarker RANTES is significantly lower in GA AMD patients compared to controls.

Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma.

The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1β (MIP-1β), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.

Bronchoalveolar lavage fluid cytokines and chemokines changes after bronchial thermoplasty in severe asthma.

Bronchial thermoplasty (BT) is a non-pharmacological intervention in severe asthma with a well-known mechanism of reducing airway smooth muscle. However, its effect on airway inflammation remains uncertain. To investigate the effect of BT on bronchoalveolar lavage fluid (BALF) cytokines and chemokines in severe asthma patients before BT, after the first BT, and 12 weeks after BT. Ten severe asthma patients were recruited, and BALF was obtained from right lower lobe before BT, after the first BT, and 12 weeks after BT. BALF analytes were measured and values were compared among the time points. Lung function, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were also measured. Tumor necrosis factor (TNF)-α concentration was significantly decreased after the first BT and significantly increased at 12 weeks after BT. Interleukin-6 (IL-6) and TNF-related apoptosis inducing ligand (TRAIL) concentration were significantly increased at 12 weeks after BT. There were no significant changes in Regulated upon activation, normal T-cell expressed and secreted (RANTES) and transforming growth factor-beta1 (TGF-β1) concentration over time after BT. At 12 weeks after BT, there were significantly greater improvements in the scores on AQLQ (3.93 ± 0.88 to 5.3 ± 0.99, p = 0.002) and ACT (13.6 ± 3.27 to 19 ± 4.44, p = 0.002). The lung function did not differ significantly between pre- and post-BT. BT has limited effect on TNF-α, IL-6, TRAIL, RANTES, and TGF- β1 in BALF suggesting that its clinical benefit is not primarily related to this local airway inflammation. The effect on long-term airway inflammation probably needs further studies.

The diagnostic importance of multiple cytokines in adult hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a category of immunological illnesses that cause out-of-control T cells and macrophages to release life-threatening cytokines. The HLH-2004 diagnostic criteria are the gold standard for HLH diagnosis, but there is a need to investigate the usefulness of various cytokines for HLH diagnosis. Patients admitted to Beijing Friendship Hospital of Capital Medical University from January 2016 to December 2020 were included in this retrospective study, with 166 patients with confirmed HLH and 142 febrile patients requiring differential diagnosis completing the sum. Multiplex cytokine assays using multifactor liquid phase microarray technology-based multifactor liquid phase microarray technology were used to detect 33 cytokines. Twenty-eight cytokines detected using the Luminex analytical platform technology were ultimately included in the analysis. Interleukin-1 receptor antagonist (IL-1 RA), IL-18, interferon-γ (IFN-γ), and interferon-induced protein 10 (IP-10) regulated upon activation normal T cell expressed and secreted (RANTES), eotaxin, growth-related oncogene α (GRO-α), and macrophage inflammatory protein-1 α (MIP-1α) were higher in the HLH group than in the non-HLH group, and the differences were statistically significant. Among them, the area under the curve (AUC) for IL-18 for HLH diagnosis was reported for the first time as 82.69%, with a sensitivity of 76.32% and a specificity of 79.61%; the AUC of IL-1 RA was 72.34%, with a sensitivity of 62.71% and a specificity of 75.97%; and the AUC of IP-10 was 71.73%, with a sensitivity of 60.14% and a specificity of 75.15%. Moreover, the AUC of the combined diagnostic tests for IL-1 RA, IL-18, IFN-γ, IP-10, and RANTES was 99.6%, with a sensitivity of 95.8% and a specificity of 98.6%. Our study concluded that multiple cytokines are valid biological markers for the diagnosis of HLH. The findings of this study remain to be validated in an external dataset.

Isorhamnetin Alleviates Airway Inflammation by Regulating the Nrf2/Keap1 Pathway in a Mouse Model of COPD

Chronic obstructive pulmonary disease (COPD) is a severely disabling chronic lung disease characterized by persistent airway inflammation, which leads to limited expiratory airflow that deteriorates over time. Isorhamnetin (Iso) is one of the most important active components in the fruit of Hippophae rhamnoides L. and leaves of Ginkgo biloba L, which is widely used in many pulmonary disease studies because of its anti-inflammatory effects. Here, we investigated the pharmacological action of Iso in CS-induced airway inflammation and dissected the anti-inflammation mechanisms of Iso in COPD mice. A mouse model of COPD was established by exposure to cigarette smoke (CS) and intratracheal inhalation of lipopolysaccharide (LPS). Our results illustrated that Iso treatment significantly reduced leukocyte recruitment and excessive secretion of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and regulated upon activation, normal T-cell expressed and secreted (RANTES) in BALF of CS-induced COPD mice in a dose-dependent manner. This improved airway collagen deposition and emphysema, and further alleviated the decline in lung functions and systemic symptoms of hypoxia and weight loss. Additionally, Iso treatment obviously improves the T lymphocyte dysregualtion in peripheral blood of COPD mice. Mechanistically, Iso may degrade Keap1 through ubiquitination of p62, thereby activating the nuclear factor erythroid 2-related factor (Nrf2) pathway to increase the expression of protective factors, such as heme oxygenase-1 (HO-1), superoxide dismutase (SOD) 1, and SOD2, in lungs of CS-exposed mice, which plays an anti-inflammatory role in COPD. In conclusion, our study indicates that Iso significantly alleviates the inflammatory response in CS-induced COPD mice mainly by affecting the Nrf2/Keap1 pathway. More importantly, Iso exhibited anti-inflammatory effects comparable with Dex in COPD and we did not observe discernible side effects of Iso. The high safety profile of Iso may make it a potential drug candidate for COPD.

Sex Differences in RANTES (CCL5) in Patients With Intermediate Age-Related Macular Degeneration (AMD) and Controls With no AMD.

PurposeTo determine if there are sex differences in levels of regulated upon activation, normal T cell expressed and secreted (RANTES) in patients with intermediate age-related macular degeneration (iAMD) and in controls with no AMD.MethodsPatients with iAMD and controls defined by multi-modal imaging were recruited into a Colorado AMD registry. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction.ResultsThe plasma level of RANTES was significantly higher in the control group in comparison with the iAMD group. When moderated by sex, RANTES was significantly lower (P = 0.005) in males (median, 4525.6 pg/mL; interquartile range, 2589–7861 pg/mL) compared with females (median, 6686 pg/mL; interquartile range, 3485–12488 pg/mL) within the iAMD cohort. No significant difference was found in levels of RANTES between males and females in the control group.ConclusionsWe found that levels of RANTES were moderated by sex in cases with iAMD with lower levels in males compared with females. The findings illustrate the importance of including sex as a biological variable in AMD research. There is a need for further studies of RANTES, stratified by sex, in the advanced phenotypes of AMD.Translational RelevanceThe biomarker RANTES identified in the plasma of patients with iAMD reflects systemic alterations when stratified by sex.

The effect of short-term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes.

BackgroundDiabetes mellitus was a chronic low‐grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short‐term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII).MethodsThirty‐three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy.ResultsFive inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin‐6 receptor (IL‐6R), regulated upon activation normal T‐cell expressed and secreted (RANTES), intercellular adhesion molecule‐1 (ICAM‐1), tissue inhibitor of metalloproteinase‐1 (TIMP‐1), and platelet‐derived growth factor type BB (PDGF‐BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL‐6R, RANTES, and ICAM‐1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM‐1, IL‐6R, RANTES, TIMP‐1, TIMP‐2, macrophage inflammatory protein‐1 beta (MIP‐1β), PDGF‐BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor‐kappa B (NF‐κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%.ConclusionsA panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL‐6R, RANTES, and ICAM‐1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL‐6R, TIMP‐2, PDGF‐BB, and TNF RII decreased after the CSII therapy.

Common points of therapeutic intervention in COVID-19 and in allogeneic hematopoietic stem cell transplantation associated severe cytokine release syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) and coronavirus disease 2019 (COVID-19) infection can both lead to severe cytokine release syndrome (sCRS) resulting in critical illness and death. In this single institution, preliminary comparative case-series study we compared clinical and laboratory co-variates as well as response to tocilizumab (TCZ)-based therapy of 15 allogeneic-HSCT- and 17 COVID-19-associated sCRS patients. Reaction to a TCZ plus posttransplant cyclophosphamide (PTCY) consolidation therapy in the allogeneic-HSCT-associated sCRS group yielded significantly inferior long-term outcome as compared to TCZ-based therapy in the COVID-19-associated group (P = 0.003). We report that a TCZ followed by consolidation therapy with a Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor given to 4 out of 8 critically ill COVID-19 patients resulted in their complete recovery. Non-selective JAK/STAT inhibitors influencing the action of several cytokines exhibit a broader effect than TCZ alone in calming down sCRS. Serum levels of cytokines and chemokines show similar changes in allogeneic-HSCT- and COVID-19-associated sCRS with marked elevation of interleukin-6 (IL-6), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1) and interferon γ-induced protein 10 kDa (IP-10) levels. In addition, levels of IL-5, IL-10, IL-15 were also elevated in allogeneic-HSCT-associated sCRS. Our multi-cytokine expression data indicate that the pathophysiology of allogeneic-HSCT and COVID-19-associated sCRS are similar therefore the same clinical grading system and TCZ-based treatment approaches can be applied. TCZ with JAK/STAT inhibitor consolidation therapy might be highly effective in COVID-19 sCRS patients.

Differences in cytokine and chemokine profiles in cerebrospinal fluid caused by the etiology of cryptococcal meningitis and tuberculous meningitis in HIV patients.

The roles of cytokines and chemokines in HIV-associated cryptococcal meningitis (HCM) and HIV-associated tuberculous meningitis (HTBM) are debatable. In sum, 34 HIV-infected patients without meningitis, 44 HCM patients and 27 HTBM patients were enrolled for study. The concentrations of 22 cytokines/chemokines in cerebrospinal fluid (CSF) were assayed at admission. Principal component analysis (PCA), Pearson's and logistic regression analyses were used to assess the role of cytokines/chemokines in HCM and HTBM. We found the levels of T helper (Th)17, Th1 [interleukin (IL)-12p40, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and TNF-β and Th2 (IL-2/4/5/6/10)] cytokines were elevated in patients with meningitis compared with those in HIV-infected patients without central nervous system (CNS) infection. Furthermore, the IL-1Ra, IL-12p40, IL-17α and monocyte chemotactic protein-1 (MCP-1) levels were higher in HCM patients, while the IFN-γ, regulated upon activation, normal T cell expressed and secreted (RANTES) and interferon-inducible protein-10 (IP)-10 levels were higher in HTBM patients. Elevated CSF concentrations of IL-17a, TNF-β, IL-5, IL-12p40 and IL-1Rα were closely related to meningitis, but elevated IP-10, MCP-1, RANTES and IFN-γ levels and CSF white blood cells (WBCs) were protective factors against HCM. Our study suggested that HIV-infected patients with low CSF WBCs have a high risk of HCM. Th1, Th2 and Th17 cytokines/chemokines mediate differences in the pathogenesis of HCM and TBM. Overexpressed proinflammatory MCP-1, RANTES, IFN-γ and IP-10 in CSF are protective factors against HCM but not HTBM.

The CCR5 and CXCR3 Pathways in Hepatitis C Virus Liver Transplanted Recipients Treated by a Direct Antiviral Agent Regimen: Informative Kinetics Profiles.

The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R (p > 0.01) and CHC (p > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC (p > 0.05 and p = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R (p < 0.01) and in CHC, but only at FU (p < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R (p < 0.03) and CHC (p < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.

RANTES/CCL5 Signaling from Jawbone Cavitations to Epistemology of Multiple Sclerosis - Research and Case Studies.

BackgroundThe role played by signaling pathways in the cell–cell communication associated with multiple sclerosis (MS) progression has become a critical area in research. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also named chemokine C-C motif ligand 5 (CCL5; R/C), is a protein that has been investigated in neuroinflammatory research due to its link to MS development.ObjectiveResearch on bone marrow defects in the jawbone (BMDJ), which morphologically presents as fatty-degenerative osteonecrosis of the jawbone (FDOJ), presents overexpression of R/C signaling in affected areas. Here, we try to elucidate the potential link between jawbone-derived R/C and MS.MethodsSeventeen BMDJ/FDOJ samples extracted from 17 MS patients, as well as samples from 19 healthy controls, were analyzed for R/C expression using bead-based Luminex® analysis. The serum R/C levels from 10 MS patients were examined. Further, bone density, histology, and R/C expression were analyzed in two clinical case studies.ResultsHigh R/C overexpression was found in all BMDJ/FDOJ samples obtained from the MS group. Serum R/C levels were also upregulated in the MS group. R/C serum levels in the MS cohort were higher than in the healthy controls. In contrast, the histology of BMDJ/FDOJ samples showed no inflammatory cells.DiscussionR/C-induced “silent inflammation” in MS is widely discussed in the scientific literature, along with R/C triggering of inflammation in the central nervous system, which might be key in the development of MS.ConclusionThe authors suspect that BMDJ/FDOJ may serve as a trigger of MS progression via R/C overexpression. As such, the dental and medical communities should be made aware of BMDJ/FDOJ in cases of MS.

Correlation analysis of expression of CC and CXC chemokines in children with autism spectrum disorder.

To investigate the relationship between the expression of CC and CXC chemokines and autism spectrum disorder (ASD).A total of 62 children with ASD (ASD group) and 60 gender- and age-matched normal children (control group) admitted to our hospital from January 2019 to January 2020 were included in the study. Monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β), regulated upon activation, normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), monokine induced by interferon (IFN)-γ (MIG), and purified human interferon-γ-induced protein-10 (IP-10) were detected in the ASD group. The correlation between the above indexes and the severity of the ASD group was analyzed.Significantly increased MCP-1 levels (P < .01) along with the markedly decreased MIP-1α and MIP-1β levels (P < .01) were detected in the venous blood of the ASD group compared with the control group. In addition, they exhibited no significant difference (yet a downward trend) in the level of RANTES (P > .05). Children in the ASD group showed significantly decreased IP-10 levels (P < .01); however, they had no noticeable change (yet a decreasing trend) in the levels of IL-8 and MIG (P > .05). MCP-1 level was positively related to the Module 1 scores of Autism Diagnostic Observation Schedule-second edition (ADOS-2), whereas the levels of Childhood Autism Rating Scale MIP-1α, MIP-1β, IL-8, IP-10, and MIG were negatively correlated with the ADOS-2 Module 1 scores (P < .01). However, no significant correlation was found between RANTES and the ADOS-2 Module 1 scores (P > .05).The levels of CC chemokines (MCP-1, MIP-1α, MIP-1β, and RANTES) and CXC chemokines (IL-8, IP-10, and MIG) are positively correlated with the pathogenesis of ASD. Inflammation is an important contributing factor to ASD.

Relative expression of proinflammatory molecules in COVID-19 patients who manifested disease severities.

Aggressive immune response, due to overexpressed proinflammatory molecules, has been characterized in coronavirus disease 2019 (COVID‐19) patients. Some of those mediators have a dual and opposite role on immune systems at play behind differential disease severities. We investigated the expression of some cytokines and chemokines in COVID‐19 patients in Bangladesh. We diagnosed the patients by detecting severe acute respiratory syndrome coronavirus 2 RNA in nasal swab samples by the real‐time RT‐PCR method. Thirty adult patients were preselected based on their disease severities and grouped into mild, moderate, and severe cases. Nine healthy volunteers participated in this study as a control. Relative expression of nine cytokines/chemokine in total leukocytes was semi‐quantified in SYBRgreen‐based real‐time quantitative reverse‐transcriptase polymerase chain reaction. We performed statistical tests on transformed log data using SPSS 24.0. At the onset of symptoms (Day 1), angiotensin‐converting enzyme 2 (ACE2) (p < 0.05) and interleukin (IL)‐6 (p > 0.05) were upregulated in all COVID‐19 groups, although the expression levels did not significantly correlate with disease severities. However, expressions of IL‐6, monocyte chemotactic protein‐1, macrophage inflammatory protein‐1α, tumor necrosis factor‐α (TNF‐α), RANTES (regulated upon activation, normal T cell expressed and secreted), and ACE2, on Day 14, were positively correlated with disease severities. Relative viral load at Day 1 showed no significant correlation with cytokine expression but had a significant positive correlation with RANTES and ACE2 expression on Day 14 (p < 0.05). Male patients had a higher level of IL‐6 than female patients on Day 1 (p < 0.05). All COVID‐19 patients showed upregulated cytokines and chemokines on Day 14 compared to Day 1 except TNF‐α. Female patients had a higher expression of ACE2 and IL‐12 on Day 14. Upregulated cytokines/chemokines at the convalescent stage, especially IL‐6, may help in targeting anticytokine therapy in post‐COVID‐19 patients' management.

Are Anti-Inflammatory Cytokines Associated with Cognitive Impairment in Patients with Insomnia Comorbid with Depression? A Pilot Study.

BackgroundTo distinguish insomnia comorbid with depression (ICD) from chronic insomnia disorder (CID) by exploring the relationship between serum levels of frequently overlooked anti-inflammatory cytokines and cognitive function.MethodsA total of 42 ICD patients, 63 CID patients, and 42 healthy control subjects were enrolled in the study. The Pittsburgh Sleep Quality Index and Hamilton Depression Rating Scale were used to assess sleep quality and depression severity, respectively. The Chinese-Beijing version of Montreal Cognitive Assessment scale (MoCA-C) and Nine-Box Maze Test (NBMT) were used to assess cognitive function. Serum levels of anti-inflammatory interleukins (IL-1RA, IL-4, IL-5, IL-10, IL-13, and IL-28A), transforming growth factor (TGF)-β1, granulocyte-macrophage colony-stimulating factor, interferon-γ, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES) were measured by enzyme-linked immunosorbent assay.ResultsThe ICD group had significantly more errors in the spatial reference task (H=2.55, Ps=0.03) and spatial working memory task (H=5.67, Ps<0.01) of the NBMT, as well as lower levels of IL-1RA (H=−2.85, Ps=0.01), IL-4 (H=−3.28, Ps<0.01), IL-5 (H=−3.35, Ps<0.01), IL-10 (H=−4.46, Ps<0.01), and IL-28A (H=−2.75, Ps=0.02) than control subjects. Compared with the CID group, the ICD group had significantly more errors in the spatial reference memory task (H=−2.84, Ps=0.01) of the NBMT, and lower levels of IL-5 (H=3.41, Ps<0.01), IL-10 (H=5.30, Ps<0.01), IL-13 (H=3.89, Ps<0.01), and GM-CSF (H=2.72, Ps=0.02). A partial correlation analysis showed that the level of one or more of IL-4, IL-5, IL-10, IL-13, and TGF-β1 was positively correlated with cognitive function (MoCA-C score and/or performance in spatial memory task) in ICD patients.ConclusionICD is a distinct condition that can be distinguished from CID based on immune dysfunction and specific types of cognitive dysfunction.