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, or RA.
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 immune cells.
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 inflammatory cells.
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 functions.
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.