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].