In this video, we will explore the downstream signaling
pathways of interleukin-6, or IL-6, and other well-studied
pathways and cytokines implicated in rheumatoid arthritis,
IL-6 is unlike most other cytokines: it signals via two
mechanisms, cis- and trans-signaling. In
both cis- and trans-signaling, the
IL-6/IL-6 receptor complex associates with gp130, creating a
functional signaling complex. The ubiquitous expression of
gp130 allows IL-6 to act directly on almost all cell types.
JAK proteins then activate and phosphorylate one another, as
well as the cytoplasmic portion of gp130. This activates 3
downstream pathways: JAK/STAT, MAPK, and PI3K—each believed
to perform unique functions in RA.
The JAK/STAT pathway is responsible for induction of
proinflammatory cytokines as well as the differentiation of
The MAPK pathway is believed to stimulate production of
proinflammatory cytokines and contribute to the degradation
of bone and cartilage.
The PI3K pathway regulates cell growth and proliferation
glucose metabolism, and the activation and recruitment of
All 3 pathways are critical to the intracellular signaling
that mediates chronic inflammation in RA.
The signaling mechanisms used by IL-6 to activate downstream
pathways differ from those of other mediators, including JAK
proteins. IL-6 only signals through its specific receptor
(IL-6R) and has primarily inflammatory functions. By
contrast, JAK proteins mediate signaling of many cytokines,
hormones, and colony-stimulating factors involved in both
inflammatory functions and other physiological
IL-6 signaling also differs from that of TNF-α and IL-1,
specifically in the way these cytokines interact with their
soluble receptors. The binding of IL-6 with its soluble
receptor forms a functional complex that promotes
downstream proinflammatory responses.
By contrast, both TNF-α and IL-1 are sequestered by their
soluble receptors, forming nonfunctional complexes
that do not cause downstream inflammatory responses.
In summary, IL-6 signaling activates the JAK/STAT,
MAP-kinase, and PI3-kinase pathways, which have distinct
functions in RA pathogenesis. IL-6 signaling is unique and
differs from JAK, TNF-α, and IL-1 signaling.
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.