Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19.

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.

Interleukin­6 signalling as a valuable cornerstone for molecular medicine (Review).

The biological abilities of interleukin­6 (IL­6) have been under investigation for nearly 40 years. IL­6 works through an interaction with the complex peptide IL­6 receptor (IL­6R). IL­6 is built with four α­chain nanostructures, while two different chains, IL­6Rα (gp80) and gp130/IL6ß (gp130), are included in IL­6R. The three­dimensional shapes of the six chains composing the IL­6/IL­6R complex are the basis for the nanomolecular roles of IL­6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL­6 have been identified. In the present review, the roles played by miRNA in the post­transcriptional regulation of IL­6 expression are evaluated. mRNAs are absorbed via the 'sponge' effect to dynamically balance mRNA levels and this has been assessed with regard to IL­6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL­6 signalling, two different IL­6 models have been proposed. IL­6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL­6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2; also known as COVID­19). In the present review, both inflammatory and cognitive IL­6 models were analysed by evaluating the cytological and histological locations of IL­6 signalling. The goal of this review was to illustrate the roles of the classic and trans­signalling IL­6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS­CoV­2 virus infection have been examined to determine the contribution of IL­6 to these disease states.

Interleukin-6 signalling in health and disease.

Biochemically, interleukin-6 belongs to the class of four-helical cytokines. The cytokine can be synthesised and secreted by many cells. It acts via a cell surface-expressed interleukin-6 receptor, which is not signalling competent. This receptor, when complexed with interleukin-6, associates with the signalling receptor glycoprotein 130 kDa (gp130), which becomes dimerised and initiates intracellular signalling via the Janus kinase/signal transducer and activator of transcription and rat sarcoma proto oncogene/mitogen-activated protein kinase/phosphoinositide-3 kinase pathways. Physiologically, interleukin-6 is involved in the regulation of haematopoiesis and the coordination of the innate and acquired immune systems. Additionally, interleukin-6 plays an important role in the regulation of metabolism, in neural development and survival, and in the development and maintenance of various cancers. Although interleukin-6 is mostly regarded as a pro-inflammatory cytokine, there are numerous examples of protective and regenerative functions of this cytokine. This review will explain the molecular mechanisms of the, in part opposing, activities of the cytokine interleukin-6.