Background

IL-6 is critical for B-cell differentiation and maturation with secretion of immunoglobulins, cytotoxic T cell differentiation, macrophage and monocyte function and production of acute phase proteins [11]. IL-6 has both a pro- and anti-inflammatory effects [5], but its pro-inflammatory mechanisms dominate in the context of CRS and ARDS [11]. IL-6 is elevated in plasma and bronchoalveolar lavage fluid (BALF) and is predictive of poor outcomes in acute lung injury patients [6, 12]. Higher molar ratio of IL-6:sIL-6R is associated with higher risk of death [3, 5]. A significant anti-inflammatory response early in ARDS may provide a key mechanism for limiting the net inflammatory response in the lungs [5].
In contrast to other receptors and antagonists (such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1)), the molar ratio of IL-6 to sIL-6R increased more than 10-fold in BALF from patients at risk for ARDS, and was approximately 100-fold higher than in normal subjects [5].
IL-6 signaling is achieved through two signaling pathways: classic and trans [Figure 1]. In classic IL-6 signaling, IL-6 first binds membrane-bound IL-6R, then the complex binds with and dimerizes the glycoprotein 130 (gp130) transmembrane protein to elicit signal transduction [13]. The transmembrane protein IL-6R is only found on certain cell types (such as macrophages, neutrophils, some T cells, and all hepatocytes).
IL-6 carries out its signaling in other cell types via a second signaling pathway: trans signaling. This alternative activation relies on the soluble IL-6R (sIL-6R), which is constitutively present in all tissue types at ng mL-1 concentrations [13]. In trans signaling, IL-6 binds sIL-6R and the complex has the ability to bind and dimerize gp130, leading to signaling. Activation of gp130 via trans-signaling is crucial for lymphocyte trafficking into the inflamed area by controlling chemokine expression [14, 15]. IL-6 trans-signaling promotes T-cell proliferation (for example, during colon cancer development) and is involved in regulating adhesion molecule expression on endothelial cells [16, 17].
One additional player in trans signaling is soluble gp130 (sgp130), which is also constitutively present [18, 19, 20]. sgp130 binds the IL‑6:sIL-6R complex with high affinity (~ 10 pM). Since sgp130 can bind to the IL-6:sIL-6R complex in the circulation, it acts as a specific inhibitor of IL-6 mediated trans signaling [21].
Taken together, sgp130 and sIL-6R serve to buffer levels of circulating IL-6 [22].