Rodriguez-Hernandez, Maria AngelesCarneros, DavidNuñez-Nuñez, MariaCoca, RamonBaena, RosarioLopez-Ruiz, Gema MCano-Serrano, Maria ElenaMartinez-Telleria, AlbertoFuentes-Lopez, AnaPraena-Fernandez, Juan ManuelGarbers, ChristophHernandez-Quero, JoseGarcia, FedericoRose-John, StefanBustos, Matilde2023-05-032023-05-032022-05-13Rodríguez-Hernández MÁ, Carneros D, Núñez-Núñez M, Coca R, Baena R, López-Ruiz GM, et al. Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19. Front Immunol. 2022 May 13;13:891456http://hdl.handle.net/10668/20586IL-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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/COVID-19IL-6IL-6 trans-signallingsoluble IL-6 receptor (sIL-6R)soluble gp130 (sgp130)soluble receptorsCOVID-19Cytokine Receptor gp130HumansInterleukin-6Receptors, Interleukin-6Severity of Illness IndexSignal Transductionresearch article35634332open accessInterleucina-6Receptor gp130 de citocinasReceptores de interleucina-6Transducción de señal10.3389/fimmu.2022.8914561664-3224PMC9137400https://www.frontiersin.org/articles/10.3389/fimmu.2022.891456/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137400/pdf