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Abstract Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of the Atypical Chemokine Receptor 1 (ACKR1) acting as scavenger for multiple chemokines and the role of tumor necrosis factor receptor-associated factor 1 (TRAFD1) in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR using 2 independent proteomics datasets paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohn’s disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

BACKGROUND: Neisseria gonorrheae and Chlamydia trachomatis are associated with mucosal inflammation and human immunodeficiency virus 1 (HIV-1) transmission. We assessed levels of inflammatory cytokines in men who have sex with men (MSM) with and without rectal gonorrhea and/or chlamydia in Lima, Peru. METHODS: We screened 605 MSM reporting condomless receptive anal intercourse for rectal N. gonorrheae/C. trachomatis using nucleic acid testing. We identified 101 cases of gonorrhea and/or chlamydia and randomly selected 50 N. gonorrheae/C. trachomatis positive cases and matched 52 negative controls. We measured levels of IL-1β, IL-6, IL-8, and TNF-α in rectal secretions. Tests for HIV-1, rectal N. gonorrheae/C. trachomatis, and mucosal cytokines were repeated after 3 and 6 months. Cytokine levels in cases and uninfected controls were compared using Wilcoxon rank-sum tests and linear regression. RESULTS: MSM with gonorrhea/chlamydia had elevated levels of all cytokines in rectal mucosa compared with matched controls (all P values .05). DISCUSSION: Rectal gonorrhea/chlamydia infection is associated with transient mucosal inflammation and cytokine recruitment. Our data provide proof of concept for rectal sexually transmitted infection screening as an HIV prevention strategy for MSM. Clinical Trials Registration. NCT03010020.

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Abstract Background The etiology of depression involves many biological and environmental factors, among which the inflammatory process is an important contributor. However, the role of pro-inflammatory cytokines in postmenopausal depression is unclear. Therefore, we aimed to explore the association between the serum concentrations of four pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) and depressive symptoms in postmenopausal women who had been receiving menopause hormone therapy (MHT) for at least 6 months and postmenopausal women who had not received MHT. Methods This study included a total of 136 Chinese postmenopausal women aged 40 to 65 years who visited the gynecology outpatient department between June 2020 and December 2022. They were divided into the POST group (n = 94) and the POST + MHT (n = 42) group. Demographic information was collected, and the Hamilton Rating Scale for Depression (HAMD) was used to assess depression. The circulating levels of IL-1β, IL-6, IL-18, and TNF-α were determined using ELISA kits. Results According to the HAMD score, 39.36% of the participants in the POST group and 14.29% in the POST + MHT group were considered to have depression. The POST + MHT group had significantly lower serum concentrations of IL-18 and TNF-α than the POST group. Multiple linear regression analysis showed that the serum IL-18 (β = 3.996, 95% CI = 0.508–7.484), and TNF-α levels (β = 4.784, 95% CI = 0.939–8.629) were significant predictors of the HAMD-24 scores in women in the POST group. In addition, age was found to be positively related with the level of depression (β = 0.531, 95% CI = 0.063–0.999). Conclusions Postmenopausal women who received MHT had a lower HAMD-24 score as well as lower serum TNF-α and IL-18 levels than women who did not receive MHT. Further, the TNF-α and IL-18 level were positively associated with the HAMD-24 score in women who had not received MHT.

Henrik Wistrand,1,2 Niina E Kaartinen,3 Pekka Jousilahti,3 Sirpa Jalkanen,4– 6 Marko Salmi,4– 6 Teemu Niiranen,2,3 Ville Lauri Langén2,7 1Faculty of Medicine, University of Turku, Turku, Finland; 2Division of Medicine, Turku University Hospital and University of Turku, Turku, Finland; 3Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland; 4MediCity Research Laboratory, University of Turku, Turku, Finland; 5Institute of Biomedicine, University of Turku, Turku, Finland; 6InFLAMES Flagship, University of Turku, Turku, Finland; 7Department of Geriatric Medicine, Turku University Hospital and University of Turku, Turku, FinlandCorrespondence: Henrik Wistrand, Email hjwist@utu.fiPurpose: The complex pathogenesis of hypertension, potentially involving inflammatory pathways, remains elusive. This study aimed to evaluate the relationship between 24-hour urinary sodium excretion and inflammatory cytokines alongside C-reactive protein (CRP) in a nationwide Finnish sample.Materials and methods: 265 participants from the FINRISK 2002 study were included in the analyses. Multivariable-adjusted associations of 24-hour urinary sodium with circulating CRP and 26 cytokines were examined.Results: 24-hour urinary sodium was not significantly associated with any of the cytokines or CRP (p ≥ 0.02 for all, significance at < 0.001). Adjustments for age, sex, serum creatinine concentration, and alcohol intake did not alter these results.Conclusion: This cross-sectional study revealed no associations between 24-hour urinary sodium and cytokine or CRP levels. This does not suggest reducing salt intake would be unbeneficial in hypertension. Additional research is required to clarify the mechanisms through which salt may induce hypertension. Assessing sodium intake in epidemiological studies is also challenging.Keywords: inflammatory cytokines, C-reactive protein, urinary sodium concentration, salt intake

Kai-li Liu,&ast; Shen-jie Xu,&ast; Si-wen Chen, Min-jie Zhang, Ni Ye, Jie Li Department of General Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li; Ni Ye, Department of General Medicine, The First Affiliated Hospital of Soochow University, No. 899 of Pinghai Road, Gusu District, Suzhou, 215006, People’s Republic of China, Tel: +86 139 6211 6580 ; +86 151 6246 0064, Email lijie_Li01@126.com; yeni0328@126.comObjective: The aim of this study was to analyze the relationship between the characteristics of the intestinal microbiota and cytokine levels in individuals with different degrees of obstructive sleep apnea-hypopnea syndrome (OSAHS) as well as to investigate intestinal microbiota imbalances in patients with OSAHS and the associated mechanisms.Methods: Based on their sleep apnea hypopnea index (AHI), a total of 37 adults were assigned to a control group, a mild OSAHS group, or a moderate-to-severe OSAHS group. Fecal samples were collected to characterize the intestinal microbiota using metagenomic next-generation sequencing (mNGS), while blood samples were collected to detect levels of interleukin-17a (IL-17a), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in each group.Results: 1. There was no significant difference in the Shannon index among the three groups (P > 0.05). The three groups showed significant difference in the relative abundance of Faecalibacterium prausnitzii and Bifidobacterium adolescentis (with F values of 3.955 and 7.24, respectively, P < 0.05), while showed no significant difference in the relative abundance of B. pseudocatenulatum, Bifidobacterium longum, Klebsiella pneumoniae, and Haemophilus parainfluenzae (P > 0.05). 2. The three groups showed significant difference in the expression of serum IL-17A and TNF-α levels (with F values of 18.119 and 10.691, respectively, P < 0.05), while showed no significant difference in the expression of IL-10, IL-6, and CRP levels (P > 0.05). 3. Multiple linear regression analysis revealed that the relative abundance of F. prausnitzii was correlated with changes in BMI and AHI (with β values of 2.585 and − 0.157, respectively, P < 0.05), while the relative abundance of B. adolescentis was correlated with changes in IL-17a (with β value of − 0.161, P < 0.05).Conclusion: The study revealed a significant correlation between intestinal microbiota abundance and cytokine levels, suggesting that gut microbiota disruption in OSAHS patients may be linked to systemic chronic inflammation.Keywords: chronic inflammation, chronic intermittent hypoxia, cytokines, intestinal microbiota, OSAHS

Systemic chronic inflammation may cause kidney injury as a result of an impaired immune response and pro-inflammatory cytokine overload due to various factors that prevent the resolution of inflammation. Therefore, it is important to determine pro-inflammatory cytokine levels by renal biopsy and to investigate treatment modalities in systemic chronic inflammation-related kidney injury. We aimed to investigate the therapeutic effect of methylprednisolone on extra-renal systemic chronic inflammation-induced renal tissue damage in terms of histopathological alterations and immunohistochemically on tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels. The mice used in this study were divided into three equally sized groups (n : 10). Group I (control) received 0.3 mL 0.9% NaCl, and group II received 0.3 mL complete Freund’s adjuvant-casein emulsion intraperitoneally for systemic chronic inflammation induction. Group III received methylprednisolone 10 mg/kg intramuscularly after intraperitoneal injection of 0.3 mL complete Freund’s adjuvant–casein emulsion. Injections were administered on days 1 and 14 of the study, and the experiment was ended 5 week after the second injections following the development of systemic chronic inflammation. Finally, kidney tissues were examined histopathologically and immunohistochemically for tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels. While normal renal histology was observed in group I, glomerulonephritis and tubulointerstitial nephritis findings were detected in group II and group III. Methylprednisolone treatment decreased the histopathologic lesions observed in group III. Immunostaining with anti-tumor necrosis factor-α, interleukin-1β and interleukin-6 showed severe immunopositivity in group II and mild immunopositivity in group III, whereas they were immunonegative in group I. Our study provides histopathological and immunohistochemical evidence supporting the decreasing effect of methylprednisolone on tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels in kidney tissue against SCI-induced renal damage due to excessive pro-inflammatory cytokine overload.