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IL-6 plays a fundamental role in driving the inflammation associated with RA, at both an articular and a systemic level

The role of IL-6

The Role of Interleukin-6 in the Pathophysiology of RA

  • IL-6, a pleiotropic cytokine, is the most abundant cytokine in the rheumatoid synovium.1,2
    • IL-6 helps to drive the recruitment and activation of inflammatory cells, such as neutrophils and macrophages, within the synovium of the joint.
    • In turn, these cells release more IL-6, establishing a pathogenic feedback loop.3–5
  • IL-6 has a pivotal role in RA signalling, exerting its effects on a wide range of cell types throughout the body by binding both the membrane-expressed and soluble forms of the IL-6 receptor (mIL-6R and sIL-6R, respectively).
  • As a result it is associated with diverse physiological effects that contribute to the system-wide pathogenesis of RA. These include:
    • Stimulating the activation of osteoclasts, which have a central role in mediating the irreversible bone and joint destruction in RA.4–7
      • Osteoblast function, which is critical for bone formation, may also be inhibited by IL-6.8
    • Inducing hepatic production of acute-phase proteins, such as hepcidin and C-reactive protein (CRP), associated with systemic inflammation.2,4
      • CRP is commonly used as a surrogate marker of systemic inflammation in RA;9 increased levels have been correlated with worsening RA symptoms.
      • In addition, elevated levels of CRP are associated with an increased risk of cardiovascular disease, the primary cause of mortality in RA patients.
      • Hepcidin is a key regulator of iron metabolism;10 it blocks the function of the iron transporter, ferroportin-1, thereby inhibiting iron absorption and release to developing red blood cells.
      • Consequently, overproduction of IL-6 can cause anaemia.11
    • Inducing differentiation of B-cells into antibody-forming plasma cells, thereby increasing the production of autoantibodies, such as RF, which target cells for immune attack by macrophages.4
    • Promoting the activation and subsequent differentiation of T-cells.
      • Recent studies have implicated IL-6 in inducing differentiation of
        T-cells into pathogenic TH17 cells – cells that play a critical role in the induction of autoimmune tissue injury – and inhibiting T-cell differentiation into protective Treg cells.12,13
    • Increasing leukocyte recruitment by activating the production of a subset of chemokines by endothelial cells and by up-regulating the expression of adhesion molecules.14
    • Driving the maturation of megakaryocytes to produce platelets, potentially inducing thrombocytosis.5

IL-6 is a key driver of chronic inflammation and autoimmunity in RA

References:

  1. Madhok R, et al. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993; 52:232–234.
  2. Choy E. Interleukin 6 receptor as a target for the treatment of rheumatoid arthritis. Ann Rheum Dis 2003; 62 (Suppl. 2):ii68–ii69.
  3. Heinrich PC, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334 (Pt 2):297–314.
  4. Choy E. Clinical experience with inhibition of interleukin-6. Rheum Dis Clin North Am 2004; 30:405–415, viii.
  5. Yoshizaki K, et al. Therapy of rheumatoid arthritis by blocking IL-6 signal transduction with a humanised anti-IL-6 receptor antibody. Springer Semin Immunopathol 1998; 20:247–259.
  6. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003; 2:473–488.
  7. Kotake S, et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996; 11:88–95.
  8. De Benedetti F, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum 2006; 54:3551–3563.
  9. Ranganath VK, et al. Age adjustment corrects for apparent differences in erythrocyte sedimentation rate and C-reactive protein values at the onset of seropositive rheumatoid arthritis in younger and older patients. J Rheumatol 2005; 32:1040–1042.
  10. Nemeth E, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113:1271–1276.
  11. Voulgari PV, et al. Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis. Clin Immunol 1999; 92:153–160.
  12. Mangan PR, et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 2006; 441:231–234.
  13. Bettelli E, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T-cells. Nature 2006; 441:235–238.
  14. Romano M, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997; 6:315–325.
  15. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423:356–361.
  16. Smolen JS, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370:1861–1874.

Figure adapted with permission from Elsevier (C) 2004.