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BBB seminar: Stefan Rose-John

The biology of Interleukin-6 and strategies of therapeutic blockade

Stefan Rose-John
Department of Biochemistry, University of Kiel, Germany

Cytokine receptors exist in membrane bound and soluble forms. The Interleukin-6/ soluble Interleukin-6 receptor (IL-6/soluble IL-6R) complex stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process 'trans-signaling'. The soluble IL-6R is generated via ectodomain shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses [1, 2]. The dimerized recombinant soluble gp130Fc fusion protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses.

Interestingly, depending on the animal model used, global blockade of IL-6 signaling by neutralizing monoclonal antibodies and selective blockade of IL-6 trans-signaling can lead to different consequences. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human diseases. Inhibition of IL-6 trans-signaling but not global IL-6 blockade was beneficial in the cecal ligation and puncture sepsis model [3]. Defense against bacterial infections relies on the membrane bound IL-6R [4]. Acute pancreatitis often results in subsequent acute lung injury, which is an inflammatory disease with high mortality. IL-6 is necessary for the inflammatory process to reach the lung and blockade of IL-6 trans-signaling is sufficient to block the disease [5].

The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, lupus erythematodes, colon cancer, ovarian cancer and pancreatic cancer that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease [1-5]. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer, and it underwent phase I clinical trials as an anti-inflammatory agent in 2013/2014. Phase II clinical trials in patients with autoimmune diseases such as inflammatory bowel disease will follow in 2015/16.

References:

  1. Jones SA, Scheller J, Rose-John S (2011) Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 121: 3375-83
  2. Calabrese L, Rose-John S (2014) IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol 10: 720-7
  3. Barkhausen T et al (2011) Selective blockade of IL-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med 39: 1407-13
  4. Hoge J et al (2013) IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling. J Immunol 190: 703-11
  5. Zhang H et al (2013) IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J Clin Invest 123: 1019-31

 

Chairperson: Øystein Bruserud <oystein.bruserud@helse-bergen.no>, Department of Clinical Science