Boster Pathways->Immunology and Inflammation

IL-6 Signaling Pathway

IL-6 signaling pathway is one of the most important immunological pathways. It has one of the highest number of publications and is monitored in almost any immunological researches.

IL-6 pathway important concepts

There Are Two Distinct IL-6 Signaling Pathways

How Do Classic And Trans-Signaling Pathways Differ?

One of the most noteworthy aspect of IL-6 signaling is that IL-6 is a pleiotropic cytokine and can elicit a variety of distinct or even contradictory physiopathological processes. This article highlights two most popularly referenced IL-6 signaling pathways, the Classic and Trans-Signaling Pathway of IL-6. IL-6 is a soluble ligand whose receptor IL-6R has two distinct forms. The membrane bound form, mbIL-6R, also called CD126 or gp80, forms a complex with IL-6 and then binds to two molecules of gp130. This binding activates the classic IL-6 signaling pathway. The soluble form, sIL-6R, binds to IL-6 with similar affinity, and then activates gp130. This binding activates the trans-signaling pathway of IL-6.

Reference: Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta (2016) 1863:1218–27. doi:10.1016/j.bbamcr.2016.03.018

Gp130 Overview

Gp130 is a glycoprotein, a common receptor and signal transducer subunit shared among all IL-6 family cytokines. Since membrane bound IL-6 can only be found on some cells, while as gp130 is ubiquitously expressed, the trans-signaling of IL-6 pathway allows IL-6 to modulate a broader variety of cells.

Same IL-6, opposite effects

Classic Il-6 signaling pathway mediates anti-inflammatory effects while trans-signaling pro-inflammatory (mostly)

It is important to note that classic IL-6 signaling promotes the synthesis of acute-phase proteins in hepatocyte, which have anti-inflammatory properties, while as IL-6 trans-signaling is pro-inflammatory. It is not however, that IL-6 trans-signaling is detrimental to host health, as it plays important roles in inflammatory reactions, for example, IL-6 trans-signaling is critical to regulate the transition from neutrophil to monocyte and prevent excessive tissue damage. Suppression of IL-6 trans-signaling also does not protect tissues from damage in many diseases. Since IL-6 plays a fundamental part in many intertwining biological processes, IL-6 classic and trans-signaling pathways play distinct pathogenetic roles in different diseases.

IL-6 pathway mechanisms

IL-6 classic and trans-signaling pathway comparison

First IL-6 binds to mbIL-6R, which then binds to two units of gp130. The resulting complex activates a variety of gp130 signaling pathways: the YxxQ motif of this complex activates JAK/STAT3 pathway; The Y759 motif activates SHP2/Gab/MAPK pathway, to name a few. The details of these pathways can be seen in the Boster pathway map. The main difference between mechanisms of the IL-6 classic and trans-signaling pathway is in the latter, IL-6 binds to sIL-6R in the body fluids and activates gp130. Since gp130 is universally expressed, this pathway can affect more cell types than its classic counterpart.

Soluble gp130 specifically inhibits IL-6 trans-signaling

Membrane bound gp130 can also be cleaved into soluble form. Sgp130 is found in human plasma in high concentration, 100–400 ng/ml according to some studies. sgp130 reacts with IL-6/sIL-6R complex with the same affinity as membrane bound gp130, and acts as an inhibitor of IL-6 trans-signaling pathway. Since sgp130 does not affect IL-6 or mbIL-6R, it can be used as an experimental tool to specifically inhibit IL-6 trans-signaling pathway.

Reference: Scheller J, Grötzinger J, Rose-John S. Updating interleukin-6 classic- and trans-signaling. Signal Transduct (2006) 6:240–59. doi:10.1002/sita.200600086

How is sIL-6R generated?

Two distinct mechanisms generate sIL-6R in humans. First metalloproteases (ADAM family, most prominently ADAM10 and ADAM17) cleaves mbIL-6R from cell membranes. Second, cells translate a differentially spliced IL-6R mRNA lacking the transmembrane and cytosolic domains. Both mechanisms release the resulting sIL-6R into the body fluids. However metalloprotease activity is believed to regulate sIL-6R levels, instead of translation of differentially spliced IL-6R mRNA. In mouse, only metalloprotease cleavage of mbIL-6R can generate sIL-6R.

IL-6 protein deep dive

IL-6 and IL-6R’s molecular structures

IL-6 contains 4 alphahelical chains arranged in a top-top-down-down topography. 3D details see this link: IL-6 interactive 3D structure

IL-6 receptor consists mostly of beta-strands forming a 3D details see this link: IL-6R interactive 3D structure

IL-6’s chromosomal location

IL-6 is located on Chromosome 7 location NC_000007.14, position 22725889 to 22732002

Family members of IL-6

A total of 10 members have been identified from the IL-6 family. They are IL-6, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotropin-1 (CT-1), cardiotrophin-like cytokine (CLC), neuropoietin (NP), IL-11, IL-27 (also known as IL-30), and IL-31. All family members share gp130 as a common receptor except IL-31. Though they share the some receptors, each family member when bound to its receptor forms different signal-transducing complex, leading to distinct downstream reactions.

IL-6’s history

Interleukin-6 (IL-6) was discovered in 1986 by Hirano T, et al, as a stimulating factor for B cell IgG production. Later it was found to be related to many biological processes including organ development, acute-phase responses, inflammation, and immune responses.

Reference: Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature (1986) 324:73–6. doi: 10.1038/324073a0; Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol (1998) 16:249–84. doi:10.3109/08830189809042997

IL-6 Effects on different cell types

Pro-inflammatory reactions mediated by IL-6:

Chondrocytes express IL-6 and can induce hepatocytic secretion of acute phase proteins, leading to acute-phase reaction.

Endothelial cells express IL-6 and can suppress inducible regulatory T cells development. With presence of TGF beta, IL-6 also promotes Th17 cell activities.

Osteoblasts express IL-6 but the effects are a mixture of anti and pro-inflammatory reactions.

Smooth muscle cells express IL-6 and help guide T cells migrate to inflammation sites.

Synoviocytes express IL-6 and promotes differentiation of CD8+ T cells into cytotoxic T cells.

T cells express IL-6 and mediates a wide variety of biological effects, depending on the environment.

Reactions not directly related to inflammation:

Epithelial cells express IL-6 and with presence of IL-3, promotes the proliferation of hematopoietic stem cells.

Fibroblasts express IL-6 that promotes megakaryocyte maturation.

Monocytes/macrophages express IL-6 that promotes hematopoietic progenitor cell growth and differentiation.