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Competing Interests: Conflicts of interest None disclosed.

BackgroundPrior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research.ObjectiveWe aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach.Materials and methodsWe selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn’s disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation.ResultsGenetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn’s disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines.ConclusionOur study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.

Aortic calcification—a marker of advanced atherosclerosis in large arteries—associates with cardiovascular mortality and morbidity. Little is known about the soluble inflamJarmatory profiles involved in large artery atherosclerosis. We investigated the correlation between aortic calcification in the abdominal aorta and cytokine levels in a cohort of peripheral artery disease patients. Aortic calcification index was measured from computed tomography exams and circulating cytokine levels were analyzed from blood serum samples of 156 consecutive patients prior to invasive treatment of peripheral artery disease. The study included 156 patients (mean age 70.7 years, 64 (41.0%) women). The mean ankle‐brachial index (ABI) was 0.64 and the mean aortic calcification index (ACI) was 52.3. ACI was associated with cytokines cutaneous T‐cell‐attracting chemokine CTACK (β 23.08, SE 5.22, p < 0.001) and monokine induced by gamma‐interferon MIG (β 9.40, SE 2.82, p 0.001) in univariate linear regression. After adjustment with cardiovascular risk factors, CTACK and MIG were independently associated with ACI, β 17.9 (SE 5.22, p < 0.001) for CTACK and β 6.80 (SE 3.33, p 0.043) for MIG. CTACK was significantly higher in the patients representing the highest ACI tertile (highest vs. middle, 7.53 vs. 7.34 Tukeys HSD p‐value 0.023 and highest vs. lowest tertile 7.53 vs. 7.29, Tukeys HSD p‐value 0.002). MIG was significantly higher in the highest tertile versus lowest (7.65 vs. 7.30, Tukeys HSD p‐value 0.027). Cytokines CTACK and MIG are associated with higher ACI, suggesting that CTACK and MIG reflect atherosclerotic disease burden of the aorta. This might further suggest the possible association with other cardiovascular morbidities. [ABSTRACT FROM AUTHOR]

Background: Human adipose-derived stromal/stem cells (hASCs) play important roles in regenerative medicine and numerous inflammatory diseases. However, their cellular heterogeneity limits the effectiveness of treatment. Understanding the distinct subtypes of hASCs and their phenotypic implications will enable the selection of appropriate subpopulations for targeted approaches in regenerative medicine or inflammatory diseases. Methods: hASC subtypes expressing dipeptidyl peptidase-4 (DPP4) were identified via fluorescence-activated cell sorting (FACS) analysis. DPP4 expression was knocked down in DPP4+ hASCs via DPP4 siRNA. The capacity for proliferation, hepatocyte differentiation, inflammatory factor secretion and T-cell functionality regulation of hASCs from DPP4−, DPP4+, and control siRNA-treated DPP4+ hASCs and DPP4 siRNA-treated DPP4+ hASCs were assessed. Results: DPP4+ hASCs and control siRNA-treated DPP4+ hASCs presented a lower proliferative capacity but greater hepatocyte differentiation capacity than DPP4− hASCs and DPP4 siRNA-treated DPP4+ hASCs. Both DPP4+ hASCs and DPP4− hASCs secreted high levels of vascular endothelial growth factor-A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6), whereas the levels of other factors, including matrix metalloproteinase (MMP)-1, eotaxin-3, fractalkine (FKN, CX3CL1), growth-related oncogene-alpha (GRO-alpha, CXCL1), monokine induced by interferon-gamma (MIG), macrophage inflammatory protein (MIP)-1beta, and macrophage colony-stimulating factor (M-CSF), were significantly greater in the supernatants of DPP4+ hASCs than in those of DPP4− hASCs. Exposure to hASC subtypes and their conditioned media triggered changes in the secreted cytokine profiles of T cells from healthy donors. The percentage of functional T cells that secreted factors such as MIP-1beta and IL-8 increased when these cells were cocultured with DPP4+ hASCs. The percentage of polyfunctional CD8+ T cells that secreted multiple factors, such as IL-17A, tumour necrosis factor alpha (TNF-α) and TNF-β, decreased when these cells were cocultured with supernatants derived from DPP4+ hASCs. Conclusions: DPP4 may regulate proliferation, hepatocyte differentiation, inflammatory cytokine secretion and T-cell functionality of hASCs. These data provide a key foundation for understanding the important role of hASC subpopulations in the regulation of T cells, which may be helpful for future immune activation studies and allow them to be customized for clinical application. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized. Objective: The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation. Methods: Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study. Results: The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01–1.04, p = 1.17e-04 and 1.03, 95% CI 1.01–1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01–1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001–1.01, p = 4.9e-2). Conclusion: The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM. Key points: Question: 1 Does type 1 diabetes(T1D) have an independent causal relationship with non-ischemic cardiomyopathy (NICM)? 2 Which inflammatory factors or diseases mediate the development of NICM in T1D? The following findings were identified in a Mendelian randomization study: Primary findings: 1 There is an independent causal relationship between T1D and NICM. Additionally, the causal relationship between T1D with complications and NICM is demonstrated. 2 Monokine induced by IFN-γ (MIG) mediates the progression from T1D to NICM. Secondary findings: BMI, hypertension, glomerular diseases, and MIG are causally associated with NICM. Meaning: All the findings are first-time discoveries in Mendelian randomization studies. The study confirms the causal relationship between T1D and NICM, while accounting for confounding factors. The MIG serves as a potential target for new preventive measure and therapy. [ABSTRACT FROM AUTHOR]

Background: Interferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART). Methods: Persons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay. Results: IP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH= 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels. Conclusion: Plasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels. [ABSTRACT FROM AUTHOR]

Objective: In the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms. Methods: A genome-wide association study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl). Results: Our results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03–1.81, P = 0.032; OR = 1.55,95%CI = 1.09–2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002–0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018). Conclusion: Our findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN. [ABSTRACT FROM AUTHOR]

Background: Autoimmune thyroid disease (AITD) ranks among the most prevalent thyroid diseases, with inflammatory cytokines playing a decisive role in its pathophysiological process. However, the causal relationship between the inflammatory cytokines and AITD remains elusive. Methods: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal connection between AITD and 41 inflammatory cytokines. Genetic variations associated with inflammatory cytokines were sourced from the FinnGen biobank, whereas a comprehensive meta-analysis of genome-wide association studies (GWASs) yielded data on Graves' disease (GD) and Hashimoto thyroiditis. Regarding the MR analysis, the inverse variance-weighted, MR-Egger, and weighted median methods were utilized. Additionally, sensitivity analysis was conducted using MR-Egger regression, MR-pleiotropy residual sum, and outliers. Results: Seven causal associations were identified between inflammatory cytokines and AITD. High levels of tumor necrosis factor-β and low levels of stem cell growth factor-β were indicative of a higher risk of GD. In contrast, high levels of interleukin-12p70 (IL-12p70), IL-13, and interferon-γ and low levels of monocyte chemotactic protein-1 (MCP-1) and TNF-α suggested a higher risk of HD. Moreover, 14 causal associations were detected between AITD and inflammatory cytokines. GD increases the levels of macrophage inflammatory protein-1β, MCP-1, monokine induced by interferon-γ (MIG), interferon γ-induced protein 10 (IP-10), stromal cell-derived factor-1α, platelet-derived growth factor BB, β-nerve growth factor, IL-2ra, IL-4, and IL-17 in blood, whereas HD increases the levels of MIG, IL-2ra, IP-10, and IL-16 levels. Conclusion: Our bidirectional MR analysis revealed a causal relationship between inflammatory cytokines and AITD. These findings offer valuable insights into the pathophysiological mechanisms underlying AITD. [ABSTRACT FROM AUTHOR]

Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-g (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors. [ABSTRACT FROM AUTHOR]

Background and Objectives: The aim of this study was to evaluate the levels of selected cytokines and their possible influence on the development of cardiovascular and pulmonary complications in patients hospitalized at the Silesian Centre for Heart Disease in Zabrze after having undergone COVID-19. Materials and methods: The study included 76 randomly selected patients from the SILCOVID-19 database. The median time from symptom onset to the study visit was 102 (86–118) days. The median age of the study group was 53 (44–60) years. Assays of a panel of 30 cytokines were carried out in the serum of patients on a Luminex100 platform using the Milliplex MAP kit from Merck KGaA Germany. Results: There were no statistically significant differences in most of the cytokines analyzed between patients with confirmed or excluded lung lesions or cardiac abnormalities. Additionally, no statistically significant differences in cytokine concentrations according to gender, age, comorbidity of diabetes, renal disease, hypertension, increased risk of thrombotic disease, or psychological disorders were demonstrated. There were high concentrations of cytokines such as platelet-derived growth actor-AA (PDGF-AA), monocyte chemoattractant protein-1 (MCP-1), monokine-induced gamma interferon (MIG), and vascular endothelial growth factor-A (VEGF-A). Conclusions: No direct impact of the dependencies between a panel of cytokines and the incidence of cardiovascular and pulmonary complications in patients hospitalized at the Silesian Centre for Heart Disease in Zabrze after having undergone COVID-19 was demonstrated. The demonstration of high levels of certain cytokines (PDGF-AA, VEGF, MIG, and IP10) that are of significance in the development of many lung diseases, as well as cytokines (MCP-1) that influence the aetiopathogenesis of cardiovascular diseases seems to be highly concerning in COVID-19 survivors. This group of patients should receive further monitoring of these cytokine levels and diagnostic imaging in order to detect more severe abnormalities as early as possible and administer appropriate therapy. [ABSTRACT FROM AUTHOR]

Background. Observational studies have suggested an association between inflammatory cytokines and Parkinson's disease (PD). This Mendelian randomization (MR) was conducted to further assess the causal correlations between inflammatory cytokines and PD. Methods. Genetic instruments associated with inflammatory cytokines were extracted from a large summary genome-wide association studies (GWAS) involving 8,293 European participants. Summary-level statistics for PD were obtained from a large-sample GWAS containing 17 studies that involved European participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted (IVW) method. Results. The IVW method indicated that basic fibroblast growth factor (FGFBasic), interleukin-2 (IL-2), and macrophage migration inhibitory factor (MIF) may be suggestively associated with the risk of PD (OR: 0.71, 95%CI: 0.52–0.96, P = 0.027; OR: 1.18, 95%CI: 1.01–1.38, P = 0.041; and OR: 1.23, 95%CI: 1.04–1.46, P = 0.018). In the reverse direction, monokine induced by interferon gamma (MIG), beta nerve growth factor (bNGF), interleukin-17 (IL-17), and interferon gamma (IFNg) are suggested to be the consequences of PD. Conclusion. Our MR analysis indicated that suggestive associations between circulating levels of FGFBasic, IL-2, and MIF and PD risk. In addition, MIG, bNGF, IL-17, and IFNg are more likely to be involved in the development of downstream PD. [ABSTRACT FROM AUTHOR]

Background: Previous studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases. Methods: Summary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results. Results: The IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 Ã--10-04, 95% CI: 5.198 Ã--10-07 - 2.129 Ã--10-01, p = 0.0151). Conclusion: This study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases. [ABSTRACT FROM AUTHOR]

Objective: Investigating the association between inflammatory cytokines and hypothyroidism remains challenging due to limitations in traditional observational studies. In this study, we employed Mendelian randomization (MR) to assess the causal relationship between 41 inflammatory cytokines and hypothyroidism. Method: Inflammatory cytokines in 30,155 individuals of European ancestry with hypothyroidism and in a GWAS summary containing 8,293 healthy participants were included in the study for bidirectional two-sample MR analysis. We utilized inverse variance weighting (IVW), weighted median (WM), and Mendelian randomization-Egger (MR-Egger) methods. Multiple sensitivity analyses, including MR-Egger intercept test, leave-one-out analysis, funnel plot, scatterplot, and MR-PRESSO, were applied to evaluate assumptions. Results: We found evidence of a causal effect of IL-7 and macrophage inflammatory protein-1β (MIP-1β) on the risk of hypothyroidism, and a causal effect of hypothyroidism on several cytokines, including granulocyte colony-stimulating factor (G-CSF), IL-13, IL-16, IL-2rβ, IL-6, IL-7, IL-9, interferon-γ-inducible protein 10 (IP10), monokine induced by interferon (IFN)-γ (MIG), macrophage inflammatory protein-1β (MIP-1β), stem cell growth factors-β (SCGF-β), stromal cell derived factor-1α (SDF-1α), and tumor necrosis factor-α (TNF-α). Conclusion: Our study suggests that IL-7 and MIP-1β may play a role in the pathogenesis of hypothyroidism, and that hypothyroidism may induce a systemic inflammatory response involving multiple cytokines. These findings may have implications for the prevention and treatment of hypothyroidism and its complications. However, further experimental studies are needed to validate the causal relationships and the potential of these cytokines as drug targets. [ABSTRACT FROM AUTHOR]

The development of ways to increase the adaptive reserves of the body and resistance to negative factors continues to be an urgent problem for physiology, which has a significant translational potential in the fields of healthcare, sports, cosmonautics and the national economy. Long-term studies of the authors have proved the promise in this respect of hypoxic hypobaric conditioning in a pressure chamber. In the present study, the principles of hypobaric conditioning were transferred to the model of normobaric intermittent hypoxia/normoxia caused by the inhalation of gas mixtures, which is widely used in practice for human interval hypoxic training. A comparative experimental analysis of molecular and cellular changes in the blood of rats in response to three-day interval hypoxic training at 9, 12, or 16% O2 in the mixture was carried out using an automated setup. It was shown that the most intense and effective 3 × 9% O2 regimen, in terms of duration and amplitude, had the greatest effect on the parameters of the clinical blood test of rats, initiating an increase in the number of erythrocytes and a decrease in the variability of their volumes, and causing a shift in the balance of lymphokine and monokine effects towards a calm activation reaction. On the first day after training at 9 and 12% oxygen, the total antioxidant capacity of serum significantly decreased, followed by rapid normalization, which fits into the dynamics of the reaction of pro- and antioxidant systems to non-damaging hypoxia. The stimulating effect of all the studied regimens of interval training on the basal and stress activity of the hypothalamic-pituitary-adrenocortical system, characteristic of conditioning, was revealed. All detected post-training changes can be attributed to the basic adaptive mechanisms that increase resistance to adverse factors. [ABSTRACT FROM AUTHOR]

Objective To analyze whether there is a potential causal association between inflammatory cytokines and various tendinopathies, including Achilles tendonitis, bicipital tendinitis, calcific tendinitis of the shoulder, gluteal tendinitis, and patellar tendinitis. Methods In this study, single nucleotide polymorphisms from the data of a large-scale genome-wide association study were selected as instrumental variables, and bidirectional Mendelian randomization as well as multivariate Mendelian randomization, were used to investigate the causal effects of inflammatory cytokines and the risk of developing Achilles tendonitis, Bicipital tendinitis, Calcific tendinitis of shoulder, Gluteal tendinitis and Patellar tendinitis. Results In forward Mendelian analyses, monocyte chemotactic protein-3 (OR=0.896,95%CI:0.806-0.995) and vascular endothelial growth factor (OR=0.917,95%CI:0.845-0.995) were potential protective factors for Achilles tendonitis, and monokine induced by interferon-γ (OR=1.158,95%CI:1.029-1.302) was a potential risk factor for Achilles tendonitis. Monocyte chemotactic protein-3 (OR=1.214,95%CI:1.034-1.426) was a potential risk factor for Bicipital tendinitis, while hepatocyte growth factor (OR=0.661,95%CI:0.489-0.893) as a potential protective factor for Bicipital tendinitis. Hepatocyte growth factor (OR=0.730,95%CI:0.557-0.957) was a potential protective factor for Calcific tendinitis of shoulder. Interleukin-13 (OR=0.828,95%CI:0.714-0.960) was a potential protective factor for Gluteal tendinitis. Interleukin-8 (OR=0.649,95%CI:0.444-0.949) as a Patellar tendinitis potential protective factor and tumor necrosis factor-α (OR=1.707,95%CI:1.085-2.685) was a potential risk factor for Patellar tendinitis. In multivariate Mendelian analysis, hepatocyte growth factor (OR=0.687,95%CI:0.511-0.924) remained a protective factor for Bicipital tendinitis. Sensitivity analyses showed that the main analyses were robust without outliers, with no significant outliers, heterogeneity, or horizontal pleiotropy. Conclusion The study suggests a potential causal relationship between inflammatory cytokines and the five tendon diseases investigated. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionThis study aims to estimate the potential causal relationship between genetically predicted levels of inflammatory cytokine and retinitis pigmentosa (RP) by performing Mendelian randomization (MR).Single nucleotide polymorphisms (SNPs) were identified as instrumental variables (IVs) from publicly available genome-wide association study datasets. Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were applied in this MR analysis. IVW and MR-Egger were used to confirm heterogeneity and pleiotropy of identified IVs. Leave-one-SNP-out analysis was used to identify SNPs with potential impact.IVW results revealed that elevated levels of Tumor Necrosis Factor Alpha (TNF-α), Macrophage Inflammatory Protein-1a (MIP1a), and Monokine Induced by Gamma Interferon (MIG) were associated with higher RP risk (OR = 2.358, p = 0.050; OR = 2.583, p = 0.013; OR = 1.851, p = 0.015), while elevated levels of Interleukin-16 (IL-16) were associated with reduced RP risk (OR = 0.723, p = 0.019). The results of heterogeneity and pleiotropy (p > 0.05) confirmed there was no pleiotropy and heterogeneity in our IVW analysis. The association of TNF-α, MIP1a, MIG and IL-16 with RP from sensitivity analyses using these two sets of restricted IVs remained stable.Our study provides evidence of potential causal relationships between several circulating cytokine levels and RP. Elevated levels of TNF-α, MIP1a, and MIG are associated with a higher risk of RP, while elevated levels of IL-16 are associated with a lower risk of RP. These cytokines may be novel biomarkers and therapeutic targets for RP. [ABSTRACT FROM AUTHOR]

Various immune mediators identified to date are associated with the development of advanced forms of diabetic retinopathy (DR), such as proliferative DR and diabetic macular edema, although the exact pathophysiological mechanisms of early stages of DR such as simple DR remain unclear. We determined the immune mediator profile in the aqueous humor of eyes with simple DR. Fifteen eyes of fifteen patients with simple DR were studied. Twenty-two eyes of twenty-two patients with cataracts and no DR served as controls. Undiluted aqueous humor samples were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 32 immune mediators comprising 13 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation, normal T cell expressed and secreted (RANTES), monokine induced by interferon-γ, basic fibroblast growth factor (bFGF), Fas ligand, granzyme A, granzyme B, interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), angiogenin, tumor necrosis factor-α, and CD40 ligand. Among the 32 immune mediators, 10 immune mediators, including bFGF, CD40 ligand, fractalkine, G-CSF, IL-6, IL-8, MIP-α, MIP-1β, and VEGF, showed significantly higher aqueous humor concentrations and the Fas ligand had significantly lower concentration (p < 0.05) in eyes with simple DR compared with control eyes. Of these 10 cytokines with significant concentration alteration, protein–protein interaction analysis revealed that 8 established an intricate interaction network. Various immune mediators may contribute to the pathogenesis of simple DR. Attention should be given to the concentrations of immune mediators in ocular fluids even in simple DR. Large-scale studies are warranted to assess whether altered aqueous humor concentrations of these 10 immune mediators are associated with an increased risk of progression to advanced stages of DR. [ABSTRACT FROM AUTHOR]

Hemophagocytic Lymphohistiocytosis (HLH) is a group of disorders culminating in systemic inflammation and multi-organ failure with high incidence of hepatic dysfunction. Overproduction of IFN-γ is the main immunopathological driver in this disorder. Monokine induced by IFN-γ (CXCL9) serves as a biomarker for disease activity and response to treatment in this disorder. However, very little is understood about the actual functional role of CXCL9 in pathogenesis in HLH. In the current study, we sought to determine the role of CXCL9 in pathogenesis in murine models of both Familial HLH (prf1−/−) and Toll Like Receptor (TLR) 9 repeated stimulation induced Macrophage Activation Syndrome (MAS), a form of secondary HLH. FHL and MAS were induced in both CXCL9 genetically deficient mice (cxcl9−/−) and controls as well as using AMG487, a pharmacological antagonist of the CXCL9 receptor, CXCR3. Results showed that CXCL9 genetic deficiency did not improve disease parameters or hepatitis in both models. Consistent with genetic ablation of CXCL9, inhibition of its receptor, CXCR3, by AMG487 did not show any significant effects in the FHL model. Taken together, inhibition of CXCL9-CXCR3 interaction does not ameliorate HLH physiology in general, or hepatitis as a classical target organ of disease. [ABSTRACT FROM AUTHOR]

Numerous studies have reported that circulating cytokines (CCs) are linked to age-related neurodegenerative diseases (ANDDs); however, there is a lack of systematic investigation for the causal association. A two-sample bidirectional Mendelian Randomisation (MR) method was utilized to evaluate the causal effect. We applied genetic variants correlated with concentrations of CCs from a genome-wide association study meta-analysis (n = 8293) as instrumental variables. Summary data of three major ANDDs [Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS)] were identified from the IEU OpenGWAS platform (n = 627, 266). Inverse-variance weighted method is the main approach to analyse causal effect, and MR results are verified by several sensitivity and pleiotropy analyses. In directional MR, it suggested that several CCs were nominally correlated with the risk of ANDDs, with a causal odds ratio (OR) of Interleukin (IL)-5 of 0.909 for AD; OR of IL-2 of 1.169 for PD; and OR of Beta nerve growth factor of 1.142 for ALS). In reverse MR, there were some suggestively causal effects of ANDDs on CCs (AD on increased Basic fibroblast growth factor and IL-12 and decreased Stem cell growth factor beta; PD on decreased Monokine induced by interferon-gamma; ALS on decreased Basic fibroblast growth factor and IL-17). The findings were stable across sensitivity and pleiotropy analyses. However, after Bonferroni correction, there is no statistically significant association between CCs and ANDDs. Through the genetic epidemiological approach, our study assessed the role and presented possible causal associations between CCs and ANDDs. Further studies are warranted to verify the causal associations. [ABSTRACT FROM AUTHOR]

Background: This cross‐sectional study aimed to evaluate salivary concentrations of macrophage activation‐related chemokines and mitogen‐activated kinase kinase (MAPKK)‐degrading proteolytic activity in children and adolescents with and without type 1 diabetes mellitus (T1DM). Methods: A total of 122 children and adolescents (65 T1DM patients, 50.8% female, mean age:10.9 years; 57 systemically healthy controls, 36.8% female, mean age: 9.5 years) were included in the study. Salivary concentrations of interferon gamma inducible protein‐10 (IP‐10), monocyte chemoattractant protein (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, macrophage‐derived chemokine (MDC), macrophage migration inhibitory factor (MIF), monokine induced by interferon gamma (MIG), and macrophage inflammatory protein‐1 alpha (MIP‐1α) were quantified using a bead‐based technique. MAPKK‐degrading proteolytic activity was detected using fluorescent peptide substrates. Results: The T1DM group had higher plaque index (PI%, p = 0.032) and bleeding on probing (BOP%, p = 0.045) scores, and lower decayed, missing, filled teeth (dmft/DMFT, p = 0.002) index scores compared to the healthy controls. Compared to the controls, salivary MCP‐1 (p = 0.007), MCP‐3 (p < 0.001), MIG (p = 0.007), and MIP‐1α (p = 0.033) concentrations were elevated whereas MCP‐4 concentrations decreased (p < 0.001) in the T1DM group. After adjusting for age, PI%, BOP%, and dmft/DMFT scores, significant differences in salivary concentrations of MIG (p = 0.033) and MIP‐1α (p = 0.017) were observed between the groups. Moreover, protease activities directed to the cleavage sites of MEK23‐18 (p = 0.001), MKK6b7‐22 (p = 0.007), MKK451‐66 (p = 0.005), MKK7b37‐52 (p = 0.034), and MKK7b69‐84 (p = 0.009) were elevated in the T1DM group. Conclusion: T1DM disrupts the salivary macrophage activation‐related chemokine profile and dysregulates proteolytic MAPKK cleavage. These findings can be an outcome of the impaired systemic immune response in T1DM. [ABSTRACT FROM AUTHOR]

Background: Sepsis occurs as a result of dysregulated host response to infection. However, cytokine adsorption therapy may restore the balance of proinflammatory and anti-inflammatory mediator responses in patients with sepsis. This study aimed to determine the cytokine adsorption ability of two different types of continuous renal replacement therapy (CRRT) hemofilters for polyethyleneimine-coated polyacrylonitrile (AN69ST) (surface-treated) and polymethylmethacrylate (PMMA) CRRT. Methods: We performed a randomized controlled trial among sepsis patients undergoing CRRT, who were randomly assigned (1:1) to receive either AN69ST or PMMA-CRRT. The primary outcome was cytokine clearance of hemofilter adsorption (CHA). The secondary endpoints were the intensive care unit (ICU) and 28-day mortalities. Results: We randomly selected 52 patients. Primary outcome data were available for 26 patients each in the AN69ST-CRRT and PMMA-CRRT arms. The CHA of high-mobility group box 1, tumor necrosis factor, interleukin (IL)-8, monokine induced by interferon-γ, and macrophage inflammatory protein were significantly higher in the AN69ST-CRRT group than in the PMMA-CRRT group (P < 0.001, P < 0.01, P < 0.001, P < 0.001 and P < 0.001, respectively). In contrast, the CHA of IL-6 was significantly higher in the PMMA-CRRT group than in the AN69ST-CRRT group (P < 0.001). In addition, the 28-day mortality was not significantly different between the two groups (50% in AN69ST-CRRT vs. 30.8% in PMMA-CRRT, P = 0.26). Conclusion: AN69ST and PMMA membranes have different cytokine CHA in patients with sepsis. Therefore, these two hemofilters may have to be used depending on the target cytokine. Trial registration number: This study was registered in the University Hospital Medical Information Network on November 1, 2017 (Trial No: UMIN000029450, https://center6.umin.ac.jp). [ABSTRACT FROM AUTHOR]

We examined the role of adipokines and pro-inflammatory cytokines in psoriatic arthritis-associated subclinical myocardial dysfunction, and the relationship between these variables and psoriatic arthritis (PsA) disease activity. Fifty-five PsA patients without cardiovascular risk factors and 25 controls underwent standard and speckle tracking echocardiography with global longitudinal strain (GLS) calculated. Standard anthropometric data and Disease Activity in Psoriatic arthritis (DAPSA) scores were recorded, with low disease activity defined as DAPSA ≤ 14 and moderate and high disease activity DAPSA > 14. Standard biochemical tests, adiponectin, resistin, leptin, tumor necrosis factor (TNF) alfa, interleukin 17 A (IL-17A), B lymphocyte chemoattractant (BLC), and monokine induced by intereferon gamma (MIG) were analyzed. Median age was 53.0 (46.0–61.0), median PsA duration 6.0 (4.0–13.0) years and median DAPSA score 25.5 (13.0–41.5). Lower GLS, tricuspid annular plane systolic excursion (TAPSE) and left ventricular ejection fraction (LVEF) were found in moderate and high PsA disease activity compared to low PsA disease activity and controls. PsA patients with GLS < 20 had higher body mass index (BMI), DAPSA score and uric acid levels, and lower adiponectin levels. Although patients with GLS < 20 had higher IL-17A levels, it was not statistically significant (P = 0.056). However, when we included healthy controls and analyzed differences based on a GLS cut-off of 20% in the entire population, the difference in IL-17A became statistically significant, 0.17 pg/mL (0.06–0.32) vs. 0.43 pg/mL (0.23–0.65), P = 0.017. The association between DAPSA score and GLS and IL-17 remained significant in multivariate analysis. Moreover, the association between GLS and IL-17 and adiponectin was significant after adjustment for age and BMI. Patients with moderate and high PsA disease activity have reduced myocardial function, lower adiponectin, and higher IL-17A levels. [ABSTRACT FROM AUTHOR]

Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with significant morbidity and mortality due to intense pulmonary inflammation. Enhanced chemokine-mediated leukocyte infiltration in lungs has been linked with unfavorable outcomes with respect to the disease. This cross-sectional study assessed the levels of chemokines among 46 MERS-CoV-infected patients (19 asymptomatic and 27 symptomatic) and 52 healthy controls using a customized Luminex human chemokine magnetic multiplex panel. The plasma levels of interferon-inducible protein (IP)-10 (568.5 ± 114.7 vs. 55.19 ± 5.85 pg/mL; p < 0.0001), macrophage inflammatory protein (MIP)-1 alpha (MIP-1A) (30.78 ± 2.81 vs. 18.16 ± 0.91 pg/mL; p < 0.0001), MIP-1B (36.63 ± 4.25 vs. 25.26 ± 1.51 pg/mL; p < 0.003), monocyte chemoattractant protein (MCP)-1 (1267 ± 309.5 vs. 390.0 ± 35.51 pg/mL; p < 0.0002), and monokine-induced gamma interferon (MIG) (28.96 ± 3.93 vs. 16.29 ± 1.69 pg/mL; p < 0.001), interleukin (IL)-8 (147.9 ± 21.57 vs. 84.63 ± 10.62 pg/mL; p < 0.004) were significantly higher in symptomatic patients than healthy controls. Likewise, the levels of IP-10 (247.6 ± 80.09 vs. 55.19 ± 5.85 pg/mL; p < 0.0002) and MCP-1 (650.7 ± 149 pg/mL vs. 390 ± 35.51 pg/mL; p < 0.02) were also significantly higher in asymptomatic patients compared to healthy controls. However, no differences were observed in the plasma levels of MIP-1A, MIP-1B, MIG, and IL-8 between asymptomatic patients and uninfected controls. Conversely, the mean plasma levels of regulated on activation normal T cell expressed and secreted (RANTES) (3039 ± 301.0 vs. 4390 ± 223 pg/mL; p < 0.001) and eotaxin (176.9 ± 30.20 vs. 296.2 ± 28.11 pg/mL; p < 0.01) were significantly lower in symptomatic MERS-CoV-infected patients compared to healthy controls. Likewise, the levels of eotaxin (162.7 ± 21.60 vs. 296.2 ± 28.11 pg/mL; p < 0.01) were also significantly lower in asymptomatic patients. Interestingly, the level of MCP-1 (2139 ± 548.2 vs. 776.5 ± 165.3 pg/mL; p < 0.004) was significantly higher in deceased symptomatic patients compared to recovered symptomatic patients. MCP-1 was the only chemokine associated with a higher risk of mortality. Symptomatic MERS-CoV-infected patients had a significant elevation of plasma chemokines and elevated MCP-1 levels were found to be associated with fatal outcomes. [ABSTRACT FROM AUTHOR]

Idiopathic granulomatous mastitis (IGM), a recurrent inflammation disease of the non‐lactating breast, has had an increasing clinical morbidity rate in recent years, and its complicated symptoms and unclear etiology make it challenging to treat. This rare benign inflammatory breast disease, centered on the lobules, represents the most challenging type of non‐puerperal mastitis (NPM), also known as non‐lactating mastitis. In this study, patients diagnosed with IGM (M, n = 23) were recruited as cases, and patients with benign control breast disease (C, n = 17) were enrolled as controls. Cytokine microarray detection measured and analyzed the differentially expressed cytokine factors between IGM and control patients. Then, we verified the mRNA and protein expression levels of the significantly changed cytokine factors using Q‐RT‐PCR, ELISA, western blot, and IHC experiments. The cytokine factor expression levels significantly changed compared to the control group. We observed a significant increase between IGM and control patients in cytokine factors expression, such as interleukin‐1β (IL‐1β), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)‐1α, MIP‐1β, tumor necrosis factor receptor 2 (TNF RII). Then, we verified the expression of these top five dysregulated factors in both mRNA and protein levels. Our results demonstrated the cytokine map in IGM and indicated that several cytokines, especially chemokines, were associated with and significantly dysregulated in IGM tissues compared to the control group. The chemokine factors involved might be essential in developing and treating IGM. These findings would be helpful for a better understanding of IGM and offer valuable insights for devising novel diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 continues to threaten public health. The virus is causing breakthrough infections in vaccinated individuals. Also, scarce information is available about cutaneous manifestations after severe acute respiratory syndrome coronavirus 2 infection. Case presentation and findings: A case of a triple-vaccinated (Pfizer) 37-year-old Hispanic American (Colombian) male who developed urticaria after Omicron BA.5.1 severe acute respiratory syndrome coronavirus 2 breakthrough infection is described. Virus isolation and whole genome sequencing along with immune and molecular assays were performed. Dermatological manifestations (skin rash and urticaria) after Omicron BA.5.1 infection were observed. Sequence analysis of the Omicron BA.5.1 isolate also revealed several important mutations. Hemogram analysis revealed leukocytosis and neutrophilia. Serology testing revealed anti-spike immunoglobulin G serum titers but negative detection of immunoglobulin M at 10 days after symptom onset. Anti-nucleocapsid, anti-spike 1 immunoglobulin G, anti-spike trimer, and anti-receptor-binding-domain immunoglobulin G and immunoglobulin E sera were detected at different titers 10 days after symptom onset. Several serum levels of chemokines/cytokines (Interferon-α, interferon-γ, interleukin-12/interleukin-23p40, interleukin-18, interferon gamma-induced protein-10, monocyte chemoattractant protein-1, monokine induced by gamma, macrophage inflammatory protein-1α, chemokine (C-C motif) ligand-5 , tumor necrosis factor-β1, Tumor necrosis factor-α) were detected, but interleukin-2, interleukin-4, interleukin-6, interleukin-8, and interleukin-17A were below the limit of detection. Interpretation and conclusions: To our knowledge, this is the first study describing skin effects of a severe acute respiratory syndrome coronavirus 2 Omicron BA.5 variant breakthrough infection in a triple-vaccinated patient in Colombia. Several important mutations were found in the spike glycoprotein of the virus isolated; these mutations are associated with immune evasion and changes in antigenic properties of the virus. Physicians overseeing coronavirus disease 2019 cases should be aware of the potential skin effects of the infection. Pathogenesis of severe acute respiratory syndrome coronavirus 2 infection and its association with proinflammatory cytokines and chemokines may enhance the development of urticaria and other skin manifestations in immunized individuals. However, further studies are needed to better understand the complexity of coronavirus disease in such situations. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is a chronic infection caused by Leishmania (L.) donovani or L. infantum parasites. Despite having the infection, most individuals never develop the clinical disease and are able to control the parasite and remain asymptomatic. However, some progress to symptomatic VL, leading to death if untreated. The host immune response has a major role in determining the progression and severity of the clinical manifestations in VL; several immune biomarkers of symptomatic VL have been described with interferon-gamma release as a surrogate biomarker of host cellular immunity. However, new biomarkers to identify asymptomatic VL (AVL) are needed for the identification of people at risk for VL activation. In our study, levels of chemokine/cytokine in the supernatants of peripheral mononuclear blood cells (PBMC) from 35 AVL+ Iraq-deployed participants, stimulated in vitro with soluble Leishmania antigen for 72 h, were assessed by a bead-based assay that allows the measurement of multiple analytes. PBMC of AVL-negative military beneficiaries were used as controls. Monocyte Chemoattractant Protein-1, Monokine Induced by Gamma Interferon and Interleukin-8, were detected at high levels in AVL+ stimulated cultures from Iraq deployers compared to uninfected controls. Measurement of chemokine/cytokine levels can identify cellular immune responses in AVL+ asymptomatic individuals. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)--for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. Methods: The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. Results: The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferongamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factoralpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). Conclusion: This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream. [ABSTRACT FROM AUTHOR]

To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP. [ABSTRACT FROM AUTHOR]

This review summarizes all the available evidence for the anti-inflammatory potential of culinary spices or their bioactives by considering in vitro, translational, and human intervention studies. An exhaustive search of the available literature was performed using PubMed, Google Scholar, and Scopus databases. The review considers information from clinical, translational, and in vitro studies especially on the commonly used spices: Curcuma longa L., Capsicum annuum L., Zingiber officinale L., Syzygium aromaticum L., Nigella sativum, and Piper nigrum L. Both in vitro studies on LPS-challenged macrophages and in vivo animal edema models have documented the anti-inflammatory potential of spice principles curcumin, capsaicin, 6-gingerol, eugenol, thymoquinone, and piperine. Studies on animal inflammation models have revealed that curcumin and capsaicin delay the onset, lower the incidence and severity of arthritis. The anti-inflammatory effects of these spices bioactives were accompanied by an inhibition of inflammatory cytokines (TNF-α, IL-1β and IL-6) and the transcription factor (NFκB). The available evidences strongly recommend that a diet rich in specific anti-inflammatory spices may reduce the inflammation and exert preventive effect on inflammation-related diseases. Although these spices are traditionally used for inflammatory disorders for centuries, their therapeutic application to prevent or treat inflammatory diseases warrants further in-depth investigation. Abbreviations CEO, Clove essential oil; COX, Cyclooxygenase; CRP, C-Reactive protein; CVD, Cardiovascular disease; DMEM, Dulbecco's modified Eagle medium; DMSO, Dimethyl sulfoxide; IL, Interleukin; IP-10, Interferon γ-induced protein-10; I-TAC, Interferon-inducible T-cell α-chemoattractant; iNOS, Inducible nitric oxide synthase; IRF, Interferon regulatory factor; LPS, Lipopolysaccharide; M-CSF, Macrophage colony-stimulating factor; MIG, Monokine induced by γ-interferon; MMP, Matrix metalloproteinase; MTT, 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NF-κB, Nuclear factor- κB; NO, Nitric oxide; NSAID, Nonsteroidal anti-inflammatory drug; PDA, Pancreatic ductal adenocarcinoma; PGE2, Prostaglandin E2; PLA2, Phospholipase A2; PPAR, Peroxisome proliferator-activated receptor; SAID, Steroidal anti-inflammatory drug; TIMP-2, Tissue inhibitor of metalloproteinase-2; TNF-α, Tumor necrosis factor-α; TQ, Thymoquinone; TX, Thromboxane; VCAM-1, Vascular cell adhesion molecule-1; VEGF, Vascular endothelial growth factor [ABSTRACT FROM AUTHOR]

• Diagnostic gaps for childhood tuberculosis are significant in low-resource countries. • Statistical analysis selected antigen 85B antibodies, interleukin-2/interferon-γ ratio, and monokine induced by interferon-γ for the scoring system. • Combination of serological and T-cell markers could enhance childhood tuberculosis screening. The diagnostic gaps for childhood tuberculosis (TB) remain considerable in settings with high TB incidence and resource constraints. We established and evaluated the performance of a scoring system based on a combination of serological tests and T-cell cytokine release assays, chosen for their ability to detect immune responses indicative of TB, in a context of high prevalence of pediatric HIV infection. We enrolled 628 consecutive children aged ≤15 years, admitted for TB suspicion. Multiple cytokine levels in QuantiFERON Gold In-Tube supernatants and antigen 85B (Ag85B) antibodies were assessed in children who tested positive with either Xpert TB or mycobacterial culture. The results were compared with those of control children. Among the biomarkers most strongly associated with TB, random forest classification analysis selected Ag85B antibodies, interleukin-2/interferon-γ ratio, and monokine induced by interferon-γ for the scoring system. The receiver operating characteristic curve derived from our scoring system showed an area under the curve of 0.95 (0.91-0.99), yielding 91% sensitivity and 88% specificity. The internal bootstrap validation gave the following 95% confidence intervals for the score performance: sensitivity 71%-97% and specificity 79%-99%. This study suggests that supplementing the QuantiFERON assay with a combination of serological and T-cell markers could enhance childhood TB screening regardless of HIV status and age. Further validation among the target population is necessary to confirm the performance of this scoring system. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: Diabetic retinopathy (DR) is a microvascular inflammatory and neurodegenerative disease. The purpose of this study was to analyze the relationship between DR severity and the levels of potential biomarkers in the serum and/or vitreous. Methods: A prospective, consecutive, controlled, observational study was performed between June 2018 and January 2020. Blood and vitreous samples were collected on the day of vitrectomy in patients without diabetes and in patients with diabetes with epiretinal membrane, macular edema, and indication for vitrectomy. Results: Transthyretin (TTR) was the only blood biomarker with levels statistically higher in patients with diabetes (p = 0.037). However, no correlation with DR severity was observed. Erythropoietin (EPO) was the only blood biomarker whose levels were associated with DR severity (p = 0.036). In vitreous samples, levels of EPO (p = 0.011), interleukin (IL)-6 (p < 0.001), IL-8 (p < 0.001), IL-17 (p = 0.022), monokine induced by interferon-γ (MIG) (p < 0.001), and interferon gamma–induced protein 10 (IP-10) (p = 0.005) were significantly higher in patients with diabetes. Additionally, in vitreous, IL-6, IL-8, MIG, and IPL-10 levels were also higher in more severe DR cases (p < 0.05). Conclusions: Among the studied biomarkers, vitreous IL-6, IL-8, MIG, and IP-10 were the ones whose levels had the strongest coherent relationship with DR severity prediction and, thus, have the best potential post-vitrectomy prognostic value. [ABSTRACT FROM AUTHOR]

Backgrounds: CXCL9, known as monokine-induced by interferon gamma (MIG), is one of the ligands of chemokine receptor CXCR3 that mediates the infiltration of lymphocytes to focal sites and suppresses tumor growth. Natural killer (NK) cells are lymphocytes belonging to the innate immunity, which can directly kill cancer cells. In addition, they have immunoregulatory activities by secreting multiple cytokines and chemokines. Objective: In the present study, we explored the role of CXCL9 in hepatocellular carcinoma (HCC) cell lines cocultured with NK-92. Two HCC cell lines, SK-Hep1 and Hep3B, were cocultured with NK-92. The cytotoxic effect of NK-92 against HCC was analyzed by CytoTox96 assay, and CXCL9 expression was measured using Human Cytokine Array, ELISA and RT q-PCR. Also, the expressions of CXCR3A and CXCR3B were analyzed by western blot. Blocking CXCL9 in Hep3B was performed using CXCL9 shRNA and recombinant human CXCL9 was used to examine the direct role of CXCL9 in NK-92. Results: The cytotoxicity of NK-92 was greater against Hep3B than against SK-Hep1, and the mRNA and protein expressions of CXCL9 were significantly higher in Hep3B when cocultured with NK-92. CXCR3B is significantly upregulated compared with CXCR3A in Hep3B and is positively affected by NK-92 coculture. CXCL9 blockade reduced the cytotoxicity of NK-92 against Hep3B. In addition, Recombinant human CXCL9 induced NK-92 chemotaxis along with increased CXCR3, PI3K (p110γ), and PLC-β3 expression and significantly increased the expressions of T-bet and STAT1, which are associated with NK cell activation. Conclusion: These findings suggest that CXCL9 can directly induce NK cells to be recruited to HCC and activate NK cytotoxicity against HCC. [ABSTRACT FROM AUTHOR]

Objectives: We analyzed the results of the QuantiFERON Glod Plus assay (QFT) and cytokine patterns associated with active tuberculosis (ATB) among patients with positive QFT. Methods: A total of 195 patients are QFT-positive, among which 24 had an ATB and 171 had a latent tuberculosis infection (LTBI). Interferon-gamma (IFN-γ) secretion was analyzed relative to interleukin-2 (IL-2), IFN-γ inducible protein or CXCL-10 (IP-10), and monokine induced by IFN-γ or CXCL-9 (MIG) secretion, and then compared between two sets of peptide antigens [tube 1 - cluster of differentiation 4 (CD4+) T cell stimulation; tube 2 - CD4+/CD8+ T cell response]. Results: Higher IFN-γ responses were measured in the ATB group (p = 0.0089). The results showed that there was a lower ratio of tube 1/tube 2 IFN-γ concentrations in the ATB group (p = 0.0009), and a median [interquartile ranges (IQR)] difference between the two sets at −0.82 IU/ml (−1.67 to 0.18) vs. −0.07 IU/ml (−0.035 to 0.11, p < 0.0001) in the ATB group compared to the LTBI group, respectively. In addition, patients with low ratios of IL-2/IFN-γ, IP-10/IFN-γ, and MIG/IFN-γ were much more likely to have ATB. Conclusion: High levels of IFN-γ secretion, preferential IFN-γ response in tube 2, and lower secretion of IL-2, IP-10, and MIG release relative to IFN-γ secretion were more likely observed in subjects with ATB. These features of T cell response may be helpful in low prevalence settings to suspect ATB in patients tested positive for IFN-γ release assays (IGRA). [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α are elevated in response to psychosocial stress; however, less is known about other inflammatory markers. We explored response to the Trier Social Stress Test (TSST) of 16 cytokines and growth factors in patients with major depressive disorder (MDD, n = 12) vs. healthy volunteers (HV, n = 16). Outcomes were baseline and post-stress levels estimated by area under the curve (AUC i) and peak change over 3 timepoints. We also explored correlations between biomarkers and clinical characteristics. Baseline concentrations were higher in MDD for platelet-derived growth factor (PDGF)-AB/BB (p = 0.037, d = 0.70), granulocyte-macrophage colony-stimulating factor (GM-CSF, p = 0.033, d = 0.52), and IL-8 (p = 0.046, d = 0.74). After TSST, AUC i was higher in MDD for GM-CSF (p = 0.003, d = 1.21), IL-5 (p = 0.014, d = 1.62), and IL-27 (p = 0.041, d = 0.74). In MDD, depression severity correlated positively with soluble CD40L (sCD40L) for AUC i (Spearman's ρ = 0.76, p = 0.004) and with baseline vascular endothelial growth factor A (VEGFA, r = 0.85, p < 0.001), but negatively with baseline monokine induced by gamma interferon (MIG, aka CXCL9; r = −0.77, p = 0.003). Effect sizes were robust in this exploratory study, although interpretation of the results must be cautious, given small sample size and multiple comparisons. Differential study of stress-induced biomarkers may have important ramifications for MDD treatment. • Exploration of 16 inflammatory markers in relation to the Trier social stress test • Levels differentiated MDD from healthy controls at baseline and after acute stress • MDD baseline levels were higher in GM-CSF, IL-8, and PDGF-AB/BB • MDD post-stress had higher GM-CSF, IL-5, and IL-27 • Depression severity correlated with baseline VEGF & MIG and predicted sCD40L response [ABSTRACT FROM AUTHOR]

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016). Patients and methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments. Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1–617) and 71 days (range, 1–490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1–24.5) in the HNSCC cohort and 19% (90% CI, 9.2–32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7–4.7) and 1.9 months (95% CI, 1.7–3.7) in the HNSCC and NSCLC cohorts. Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing. [ABSTRACT FROM AUTHOR]

ABSTRACT Tuberculous meningitis (TBM) is a severe infectious disease affecting the central nervous system, causing high mortality and disability. However, current diagnostic methods for TBM using cerebrospinal fluid (CSF) lack sensitivity and predictive biomarkers for prognosis. We conducted a study on cytokine profiles in CSF and serum samples from TBM patients to identify disease-specific biomarkers. Patients were categorized into three groups: TBM (n = 17), cryptococcal meningitis (n = 10), and non-infection (n = 6), and cytokine levels were quantified using a 48-plex panel. After treatment, we observed a significant reduction in the levels of 12 cytokines, indicating their potential use as biomarkers for treatment monitoring. Among them, monokine induced by interferon-γ (MIG) and interleukin-18 showed significant differences in serum or CSF cytokine levels compared to the control groups. CSF levels of MIG in TBM patients were negatively correlated with the CSF/blood glucose ratio (r = −0.4728, P = 0.0475). Positive correlations were found between CSF leukocyte counts and several cytokines, including fibroblast growth factor-basic, granulocyte colony-stimulating factor (G-CSF), monocyte chemotactic protein-3, macrophage inflammatory protein 1 alpha (MIP-1α), and tumor necrosis factor alpha. G-CSF and MIP-1α were also positively correlated with CSF protein levels. Receiver operating characteristic curve analysis revealed that MIG exhibited the highest area under the curve of 0.92 [95% confidence interval (CI) 0.82–1.00] with a sensitivity of 0.85 (95% CI 0.58–0.97) and a specificity of 0.87 (95% CI 0.62–0.98), making it a promising diagnostic biomarker for TBM. Our study provides valuable insights into TBM’s pathogenesis and identifies potential biomarkers for diagnosis and evaluating treatment monitoring. IMPORTANCE Tuberculous meningitis is a life-threatening infection with high mortality and disability rates. Current diagnostic methods using cerebrospinal fluid (CSF) samples have limited sensitivity and lack predictive biomarkers for evaluating prognosis. This study’s findings reveal excessive activation of the immune response during tuberculous meningitis (TBM) infection. Notably, a strong negative correlation was observed between CSF levels of monokine induced by interferon-γ (MIG) and the CSF/blood glucose ratio in TBM patients. MIG also exhibited the highest area under the curve with high sensitivity and specificity. This study suggests that MIG may serve as a novel biomarker for differentiating TBM infection in CSF or serum, potentially leading to improved diagnostic accuracy and better patient outcomes.