Based on animal models, they were able to prove that the inflammatory messenger Interleukin-6 (IL-6) propels both lung diseases. Experiments showed that this takes place via a soluble IL-6 receptor with a special signal path, so-called IL-6 trans-signalling“. At the same time, it was possible to use an IL-6 trans-signalling inhibitor to halt disease progression. These results, published in the American Journal of Respiratory and Critical Care Medicine (July 2016) and in Cancer Research (January 2016) enable new therapeutic options. Professor Stefan Rose-John is convinced of this: “This is really spectacular. I am sure that it is worthwhile to develop this further.”
In both studies, Professor Brendan Jenkins and his team showed that an inflammatory messenger, Interleukin 6 (IL-6), propels the disease progression through a signal pathway known as trans-signalling. The Kiel Biochemistry Professor Stefan Rose-John discovered this signal pathway around 20 years ago, and named it trans-signalling, in contrast to classical signalling. “The special thing about trans-signalling is that thereby Interleukin 6 also works on those cells that don’t have their own IL-6 receptor,” explained Rose-John, who initiated the projects together with Brendan Jenkins. “What distinguishes my group, and what makes us highly valuable partners for many laboratories worldwide, is that we have the best tools available to do research in IL-6 signalling. Only with our tools you can answer the question of whether it takes place via the membrane-bound or soluble receptor, and this is important.”
The goal of this study – and further studies – is to identify additional diseases in which IL-6 is involved. In previous investigations into the inflammation of joints and intestine, as well as into the growth of cancer cells, it was determined that the disease-causing effects of Interleukin 6 are primarily conveyed via IL-6 trans-signalling. This has also been confirmed now by Jenkins’ studies on lung cancer and emphysema. “Trans-signalling and IL-6 have very important effects on lung diseases. They are the master regulators and can be specifically targeted by sgp130Fc,” explained the Australian immunologist, who was surprised by the close link between the two very different lung diseases. This is because emphysema is characterised by the loss of lung tissue, and lung cancer by uncontrolled growth of tissue.
The protein sgp130Fc is a potent inhibitor of IL-6 trans-signalling. It was developed at the Institute of Biochemistry at Kiel University under the leadership of Stefan Rose-John, and is currently being clinically tested as a therapy for people with chronic inflammatory bowel diseases. The studies, which have now been published show that, in principle, sgp130Fc is also a therapy option for people with certain lung cancer diseases (KRAS gene mutations) or with emphysema.
Anti-inflammatory effect – protein sgp130Fc
The special thing about sgp130Fc is: it specifically only switches off IL-6 trans-signalling (which triggers and propels chronic inflammation), without basically inhibiting all the other functions of IL-6. Additional important functions of Interleukin-6 in the immune system, the metabolism, and in liver regeneration, are largely unaffected. This makes it significantly different from other molecules which completely block Interleukin-6, such as the monoclonal antibody Tocilizumab, which is used in the therapy of Rheumatoid Arthritis.
The protein sgp130Fc imitates soluble gp130, which occurs in the blood naturally. However, by linking the gp130 molecules in pairs, it is significantly more effective than the natural soluble protein. Together with the soluble IL-6 receptor, it attaches to Interleukin-6 in the blood. The complex can therefore not bind with the membrane-bound gp130, and cannot trigger trans-signalling, thus inhibiting inflammation.
Ruwanpura S.M. et al. Therapeutic Targeting of the IL-6 Trans-signalling/mTORC1 Axis in Pulmonary Emphysema. Am J Respir Crit Care Med. First published online 02 Jul 2016 as DOI: 10.1164/rccm.201512-2368OC
Brooks G.D. et al. IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis.
Cancer Res. 2016 Feb 15;76(4):866-76. doi: 10.1158/0008-5472.CAN-15-2388. Epub 2016 Jan 7.
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Stefan Rose-John, Cluster of Excellence „Inflammation at Interfaces“ and Institute of Biochemistry at Kiel University. Photo: Dr. Tebke Böschen/ Kiel University
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In principle, Interleukin-6 (IL-6) works via two different signal paths. In the “classical path”, IL-6 docks on to its receptor, which is bound to the cell membrane. This complex binds with gp130 and thereby triggers the signal to activate the immune system. This signal path is restricted to cells that carry an IL-6 receptor. This is only a few types of cells, however, primarily immune cells and liver cells. Nevertheless, other cells can also respond to the signal from IL-6. To enable this, IL-6 binds with the “soluble” IL-6 receptor found in the blood and in inflamed tissue. This second signal path, so-called trans-signalling, is decisive for inflammation processes in diseases. Externally-supplied sgp130Fc binds with the soluble complex, so that no trans-signalling is triggered.
Prof. Dr. Stefan Rose-John
Institute of Biochemistry
Tel.: +49 (0)431/880-3336
Cluster of Excellence „Inflammation at Interfaces“
Scientific Office, Head: Dr. habil. Susanne Holstein
Press and Communications, Sonja Petermann, Text: Kerstin Nees
Postal address: Christian-Albrechts-Platz 4, 24118 Kiel, Germany
Tel.: +49 (0)431 880-4850, Fax: +49 (0)431 880-4894
The Cluster of Excellence „Inflammation at Interfaces“ has been funded since 2007 by the Excellence Initiative of the German Government and the federal states with a total budget of 68 million Euros. It is currently in its second phase of funding. Around 300 cluster members are spread across the four locations: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH)), Lübeck (University of Lübeck, UKSH), Plön (Max Planck Institute for Evolutionary Biology) and Borstel (Research Center Borstel (FZB) – Center for Medicine and Biosciences) and are researching an innovative, systematic approach to the phenomenon of inflammation, which can affect all barrier organs such as the intestines, lungs and skin.