Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Abstract

Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.

Reviving the mutual impact of SARS-COV-2 and obesity on patients: From morbidity to mortality

“…Contrasting IL-6R that is only articulated on a small number of cells, while the gp130 is found on every cell surface [70] . Cells which are shown to have both complex constituents are directly receptive to IL-6, which is known as the traditional signalling mechanism, while the cells lacking IL-6R react to IL-6 coupled to sIL-6R (solvable form of IL-6R), which is known as the trans signalling mechanism 69 , 70 . By the assistance of metalloproteinase and disintegrin enzyme, sIL-6R is produced by proteolytic breakdown of IL-6R bounded to the membrane [71] .…”

“…It works through dual signalling mechanisms: the classic signalling mechanism, which is accountable for IL-6's anti-inflammatory effects, and the trans-signalling mechanism, which is responsible for pro-inflammatory activity [69] . The complex of a type I signal transducer protein (gp130) and an IL-6 binding type I glycosylated transmembrane protein (IL-6 receptor) is responsible for IL-6's biological function [70] . Contrasting IL-6R that is only articulated on a small number of cells, while the gp130 is found on every cell surface [70] .…”

“…The complex of a type I signal transducer protein (gp130) and an IL-6 binding type I glycosylated transmembrane protein (IL-6 receptor) is responsible for IL-6's biological function [70] . Contrasting IL-6R that is only articulated on a small number of cells, while the gp130 is found on every cell surface [70] . Cells which are shown to have both complex constituents are directly receptive to IL-6, which is known as the traditional signalling mechanism, while the cells lacking IL-6R react to IL-6 coupled to sIL-6R (solvable form of IL-6R), which is known as the trans signalling mechanism 69 , 70 .…”

“…In individuals with a BMI of 25 or below, adiponectin/leptin demonstrated high discriminatory accuracy for COVID-19 pneumonia with a threshold of 2.23 [74] . It's an anti-inflammatory hormone that has a negative relationship with the levels of IL-6 and CRP in overweight people (lesser adiponectin with raised inflammatory intermediaries) [70] . The results were supplementarily supported by the fact that obese people who lost weight saw their IL-6, CRP, and adiponectin levels reverse [75] .…”

“…In COVID-19 subjects, cytokine storm is a leading cause of mortality. A higher amount of cytokines, interferon (IFN), and IL-6 characterise this immune hyperactivation phenomenon, which results in immunological activation-related consequences and symptoms [70] . Obesity has a negative impact on the anatomy and physiology of upper respiratory activity, respiratory drive and mechanics, all of which have a direct impact on the respiratory function of obese patients [80] .…”