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Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes associated with high mortality and disability rates. Inflammation has emerged as a key pathological mechanism in DKD, prompting interest in novel therapeutic approaches targeting inflammatory pathways. Interleukin-6 (IL-6), a well-established inflammatory cytokine known for mediating various inflammatory responses, has attracted great attention in the DKD field. Although multiple in vivo and in vitro studies highlight the potential of targeting IL-6 in DKD treatment, its exact roles in the disease remains unclear. This review presents the roles of IL-6 in the pathogenesis of DKD, including immunoinflammation, metabolism, hemodynamics, and ferroptosis. In addition, we summarize the current status of IL-6 inhibitors in DKD-related clinical trials and discuss the potential of targeting IL-6 for treating DKD in the clinic.

Interleukin-6 (IL-6) is a pleiotropic cytokine that not only regulates the immune and inflammatory response but also affects hematopoiesis, metabolism, and organ development. IL-6 can simultaneously elicit distinct or even contradictory physiopathological processes, which is likely discriminated by the cascades of signaling pathway, termed classic and trans-signaling. Besides playing several important physiological roles, dysregulated IL-6 has been demonstrated to underlie a number of autoimmune and inflammatory diseases, metabolic abnormalities, and malignancies. This review provides an overview of basic concept of IL-6 signaling pathway as well as the interplay between IL-6 and renal-resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Additionally, we summarize the roles of IL-6 in several renal diseases, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, acute kidney injury, and chronic kidney disease.

Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off-label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice.

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second greatest cause of cancer deaths. About 75% of all CRCs are sporadic cancers and arise following somatic mutations, while about 10% are hereditary cancers caused by germline mutations in specific genes. Several factors, such as growth factors, cytokines, and genetic or epigenetic alterations in specific oncogenes or tumor-suppressor genes, play a role during the adenoma–carcinoma sequence. Recent studies have reported an increase in interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels in the sera of patients affected by colon cancer that correlate with the tumor size, suggesting a potential role for IL-6 in colon cancer progression. IL-6 is a pleiotropic cytokine showing both pro- and anti-inflammatory roles. Two different types of IL-6 signaling are known. Classic IL-6 signaling involves the binding of IL-6 to its membrane receptor on the surfaces of target cells; alternatively, IL-6 binds to sIL-6R in a process called IL-6 trans-signaling. The activation of IL-6 trans-signaling by metalloproteinases has been described during colon cancer progression and metastasis, involving a shift from membrane-bound interleukin-6 receptor (IL-6R) expression on the tumor cell surface toward the release of soluble IL-6R. In this review, we aim to shed light on the role of IL-6 signaling pathway alterations in sporadic colorectal cancer and the development of familial polyposis syndrome. Furthermore, we evaluate the possible roles of IL-6 and IL-6R as biomarkers useful in disease follow-up and as potential targets for therapy, such as monoclonal antibodies against IL-6 or IL-6R, or a food-based approach against IL-6.

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.

The biological abilities of interleukin-6 (IL-6) have been under investigation for nearly 40 years. IL-6 works through an interaction with the complex peptide IL-6 receptor (IL-6R). IL-6 is built with four α-chain nanostructures, while two different chains, IL-6Rα (gp80) and gp130/IL6β (gp130), are included in IL-6R. The three-dimensional shapes of the six chains composing the IL-6/IL-6R complex are the basis for the nanomolecular roles of IL-6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL-6 have been identified. In the present review, the roles played by miRNA in the post-transcriptional regulation of IL-6 expression are evaluated. mRNAs are absorbed via the 'sponge' effect to dynamically balance mRNA levels and this has been assessed with regard to IL-6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL-6 signalling, two different IL-6 models have been proposed. IL-6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL-6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; also known as COVID-19). In the present review, both inflammatory and cognitive IL-6 models were analysed by evaluating the cytological and histological locations of IL-6 signalling. The goal of this review was to illustrate the roles of the classic and trans-signalling IL-6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS-CoV-2 virus infection have been examined to determine the contribution of IL-6 to these disease states.

[This corrects the article DOI: 10.3389/fcimb.2025.1605446.].

Ovarian cancer is the most fatal gynecological cancer in the USA and the fifth most common cancer-related cause of death in women. Inflammation has been shown to play many roles in ovarian cancer tumor growth, with the proinflammatory cytokine interleukin-6 (IL-6) having been established as a key immunoregulatory cytokine. Ovarian cancer cells continuously secrete cytokines that promote tumorigenicity in both autocrine and paracrine fashions while also receiving signals from the tumor microenvironment (TME). The TME contains many cells including leukocytes and fibroblasts, which respond to proinflammatory cytokines and secrete their own cytokines, which can produce many effects including promotion of chemoresistance, resistance to apoptosis, invasion, angiogenesis by way of overexpression of vascular endothelial growth factor, and promotion of metastatic growth at distant sites. IL-6 and its proinflammatory family members, including oncostatin M, have been found to directly stimulate enhanced invasion of cancer cells through basement membrane degradation caused by the overexpression of matrix metalloproteinases, stimulate promotion of cell cycle, enhance resistance to chemotherapy, and cause epithelial-to-mesenchymal transition (EMT). IL-6 has been shown to activate signaling pathways that lead to tumor proliferation, the most studied of which being the Janus kinase (JAK) and STAT3 pathway. IL-6-induced JAK/STAT activation leads to constitutive activation of STAT3, which has been correlated with enhanced tumor cell growth and resistance to chemotherapy. IL-6 has also been shown to act as a trigger of the EMT, the hypothesized first step in the metastatic cascade. Understanding the important role of IL-6 and its family members' effects on the pathogenesis of ovarian cancer tumor growth and metastasis may lead to more novel treatments, detection methods, and improvement of overall clinical outcomes.

Zhiping Yu,1,* Ji Liu,2,* Letian Chen,1 Ming Jiang1 1Department of Respiratory and Critical Care Medicine, Yingtan People’s Hospital, Yingtan, Jiangxi, People’s Republic of China; 2Department of Hematology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Letian Chen, Department of Respiratory and Critical Care Medicine, Yingtan People’s Hospital, Yingtan, Jiangxi, People’s Republic of China, Email 407880624@qq.com Ming Jiang, Department of Respiratory and Critical Care Medicine, Yingtan People’s Hospital, Yingtan, Jiangxi, People’s Republic of China, Email 527606024@qq.comObjective: This study aims to assess the predictive value of interleukin-6 (IL-6) as a biomarker in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD).Methods: A total of 361 RA patients (236 RA non-ILD and 125 RA-ILD patients) are included in the study, and stratified analysis is performed according to age and gender. The RA-ILD group is divided into mild ILD, moderate ILD, and severe ILD groups based on HRCT score. Using logistic regression analysis to investigate the risk association between IL-6 and rheumatoid arthritis-associated interstitial lung disease (RA-ILD), and employing receiver operating characteristic (ROC) to determine the value of IL-6 for distinguishing RA-ILD. Pearson’s analysis and linear regression are used to analyze the association between IL-6 and RA disease activity, High-Resolution Computed Tomography (HRCT) scores, and Krebs Von den Lungen-6 (KL-6).Results: The level of IL-6 in the RA-ILD group is higher than that in the RA non-ILD group (p < 0.001). The OR of IL-6 associated with the risk of ILD is 1.03 (p < 0.001). IL-6 demonstrated significant diagnostic utility in distinguishing RA-ILD patients from RA patients without ILD, with an area under the receiver operating characteristic curve (AUC) of 0.810 (95% CI: 0.767– 0.854; p < 0.001). At the best cutoff value of 8.87 pg/mL, IL-6 exhibited a sensitivity of 94.4% and specificity of 63.6%. There is no statistically significant difference in IL-6 among the ILD subgroups (p > 0.05). Pearson correlation analysis and multiple linear regression analysis show that IL-6 is significantly positively correlated with Disease Activity Score-28 (DAS28), but does not significantly correlate with HRCT score and KL-6.Conclusion: IL-6 may be used as a new peripheral blood biomarker to predict RA-ILD.Keywords: IL-6, RA-ILD, biomarker, inflammation, cytokine

The purpose of this case report was to demonstrate the efficacy of Tocilizumab in the treatment of severe coronavirus disease 2019 (COVID-19) in obese patients who presented with a week's history of fever and one day of shortness of breath (SOB). It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). COVID-19 has rapidly spread throughout the world, resulting in a global pandemic. Severe COVID-19 causes proinflammatory cytokine release and is associated with a high morbidity and mortality rate. Furthermore, obesity is an independent risk factor for developing severe COVID-19 complications with a high mortality. Stopping this cascade early in the disease's progression has resulted in a significant improvement in outcome. Tocilizumab in conjunction with systemic corticosteroids as part of the standard of care for halting pro-inflammatory cytokine cascades in early disease courses and prone positioning has been shown to improve respiratory parameters while also reducing the need for mechanical ventilation and Intensive Care Unit (ICU) stay (14 days as in our case).