In this video, we will discuss the unique dual-signaling
mechanism of interleukin-6, or IL-6, which enables it to
affect many cell types and cause chronic inflammation and
the clinical manifestations of rheumatoid arthritis, or RA.
Unlike most cytokines, the dual-signaling mechanism of IL-6
includes cis-signaling and trans-signaling.
Cis-, or classical signaling, utilizes
membrane-bound receptors that are present on a limited
number of cells, including hepatocytes and leukocytes (for
example, neutrophils, monocytes, macrophages, and some
lymphocytes). Cis-signaling is important for
anti-inflammatory, homeostatic, and protective functions.
Trans-signaling uses a soluble IL-6 receptor to
interact with many additional cells that do not have
membrane-bound receptors, such as osteoclasts,
fibroblast-like synoviocytes, endothelial cells, adipocytes,
and neural cells. This is the predominant IL-6 signaling
mechanism observed in inflammatory disease states such as
A key piece of IL-6 signaling- both cis and
trans – is the ubiquitously expressed
signal-transducing gp130. It is important to note that gp130
is used in the signaling of many other groups of cytokines,
such as IL-11 and IL-27.
The complex of IL-6 and its receptor must engage gp130.
Alone, IL-6 binding to its receptors will not adequately
initiate signaling. When the membrane-bound or the soluble
IL-6 receptor/IL-6 complex binds to gp130, homodimerization
is induced. This conformational change activates a pair of
JAK proteins, which then phosphorylate each other through a
process referred to as autophosphorylation. Then they
phosphorylate the cytoplasmic tail of the gp130 receptor and
initiate downstream signaling.
There are three distinct downstream signaling pathways of
IL-6: The JAK/STAT pathway, MAP-kinase pathway, and
PI3-kinase pathway. All 3 pathways are critical to IL-6
intracellular signaling in RA that ultimately mediates
downstream effects indicative of RA.
The dual signaling of IL-6 allows it to affect almost every
cell type, organ, and tissue. Elevated IL-6 levels affect:
Hepatocytes, which can contribute to the acute-phase
response, restrict the supply of iron to hemoglobin
synthesis, and cause metabolic dysregulation. Osteoclasts
and fibroblast-like synoviocytes, which leads to bone
resorption. Neural and glial cells, which leads to fatigue,
pain, altered sleep, morning stiffness, and affects mood.
Endothelial cells, which leads to cardiovascular effects.
Adipocytes, which leads to metabolic dysregulation.
In summary, cis- and trans-signaling of
IL-6 explains its pleiotropic nature; that is, its ability
to affect almost all cell types, organs, and tissues.
To find out more about IL-6, please browse additional videos
in this series on RAandIL6.com. This video was brought to
you by Sanofi Genzyme and Regeneron Pharmaceuticals.