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.

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 proteins can also have nonspecific downstream effects in RA11
    • JAK proteins mediate signaling for ~60 cytokines, hormones, and colony-stimulating factors that are implicated in RA and play a role in other 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.

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.