Pathway
Activation

IL-6 activates downstream signaling pathways
that have a broad and distinct role in articular and systemic manifestations of RA1-4

Through its dual signaling mechanism, IL-6 is able to exert pleiotropic effects in patients with RA. The interaction of IL-6 receptors via cis- and trans-signaling with the signal-transducing protein, gp130, creates a functional, hexameric signaling complex. These actions activate constitutively bound JAK proteins, which then initiate a downstream signaling cascade.1-4

3 pathways downstream of IL-6 contribute to the pathophysiology of RA1-3,5,6

The 3 pathways downstream of IL-6 contribute to the pathophysiology of RA. The first is MAPK which regulates the pro-inflammatory cytokines. The second pathway is JAK-STAT, it mediates gene expression and cell differentiation. JAK proteins primarily affect this pathway and potentially phosphorylate other kinases. The third is PI3K and it upregulates cell growth and survival and glucose metabolism. The 3 pathways downstream of IL-6 contribute to the pathophysiology of RA. The first is MAPK which regulates the pro-inflammatory cytokines. The second pathway is JAK-STAT, it mediates gene expression and cell differentiation. JAK proteins primarily affect this pathway and potentially phosphorylate other kinases. The third is PI3K and it upregulates cell growth and survival and glucose metabolism.

MAPK=mitogen-activated protein kinase; JAK-STAT=Janus kinase-signal transducer and activator of transcription; PI3K=phosphoinositide 3-kinase.

LISTEN NOW:
A deeper dive into IL-6 pathway activation and downstream signaling in RA
by Dr Alvin Wells

Dr Wells was compensated and/or received an honorarium from Sanofi Genzyme in connection with this presentation. This content was jointly developed by Dr Wells and Sanofi Genzyme.

Cell signaling and downstream effects in RA

  • The binding of IL-6 with its soluble receptor forms a functional complex that activates downstream pro-inflammatory signaling7-10
  • By contrast, both TNF-α and IL-1 form nonfunctional complexes with their soluble receptors, thereby preventing pro-inflammatory signaling by the complexes7-10
  • JAK protein family is involved in a cascade of intracellular signaling11
    • It is involved in activating ~60 cytokines, colony-stimulating factors, and hormones to carry out vital physiological functions5,11
Inflammatory functions: IL6, JAK1 JAK2. TYK2, JAK3 Inflammatory functions: IL6, JAK1 JAK2. TYK2, JAK3

IL=interleukin; EPO=erythropoietin; TPO=thyroid peroxidase; GM-CSF=granulocyte-macrophage colony-stimulating factor; GH=growth hormone; IFN=interferon; JAK=Janus kinase; TYK=tyrosine kinase.

Discovering IL-6 Activation
of Multiple Inflammatory
Pathways in RA

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.

References: 1. Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720-727. Published correction appears in Nat Rev Rheumatol. 2014;10(12):i. 2. Eulenfeld R, Dittrich A, Khouri C, et al. Interleukin-6 signalling: more than Jaks and STATs. Eur J Cell Biol. 2012;91(6-7):486-495. 3. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605-635. 4. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-888. 5. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-328. 6. Zheng X, Ke Y, Feng A, et al. The mechanism by which amentoflavone improves insulin resistance in HepG2 cells. Molecules. 2016;21(5):624. 7. Colmegna I, Ohata BR, Menard HA. Current understanding of rheumatoid arthritis therapy. Clin Pharmacol Ther. 2012;91(4):607-620. 8. Sha Y, Markovic-Plese S. A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self Nonself. 2011;2(1):35-42. 9. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-442. 10. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis—shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63-68. 11. Virtanen AT, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: prospects in inflammatory and autoimmune diseases. BioDrugs. 2019;33(1):15-32.