11:54pm Friday 24 November 2017

Tumor Necrosis Factor – Discovered 40 Years Ago

What makes TNF so important?
Claude: TNF is important in inflammation and cancer and is therefore a prized therapeutic target. Hundreds of thousands of patients are treated with anti-TNF biologicals, which are among the top 10 medications that bring in the most money. These are medications against rheumatoid and psoriatic arthritis, psoriasis, ulcerative colitis and Crohn’s disease. Because of the many side effects, use of TNF as an anti-cancer medication is limited to local treatment of tumors of the limbs.

TNF was discovered in the mid-1970s by researchers studying cancer and severe inflammation. Walter Fiers played a very important role in this regard. Because TNF is one of the first cytokines discovered, the research had a head start and TNF is by far the bestknown cytokine.

Rudi: Understanding of the TNF signal transduction network also establishes a paradigm for clarifying other signal transduction pathways. For example, the unravelling of TNF-induced NF-κB activation forms the foundation of our knowledge of other receptorinduced signals that result in activation of NF-κB, one of the most important transcription factors in immune responses.

Peter: The study of TNF-related signal transduction has also led to the unravelling of apoptosis and
to the identification of caspases and insight into their activation mechanisms, and more recently to
the identification of RIP kinases and their role in apoptosis and necroptosis, a new form of cell death due to regulated necrosis. More knowledge of TNF’s role in cell death may result in a revival of TNF as an anti-cancer agent. The great challenge will be to keep the pro-inflammatory effects of TNF under control.

What role does TNF play in our body?
Claude: TNF is as good as absent in homeostasis. But when homeostasis is disrupted, e.g. in the presence of infection or auto-immune diseases, cells make very low concentrations of TNF. This is sufficient for a strong reaction, because the receptors for TNF are found on all cells and TNF works in very low concentrations. TNF stimulates other cells to form an infection pattern; it activates white blood cells and endothelial cells, resulting in local inflammation, it induces the expression of other cytokines, such as Interleukine-1 (IL1) and IL6, which results in fever, and TNF results in cell death.

Rudi: TNF is produced very early during an immunological response and activates more than 1,000 other genes that are relevant for this response. Increased TNF production is linked to a wide range of diseases, including cardiovascular, neurological, metabolic and autoimmune diseases.

Peter: It was recently rediscovered that TNF can also be cytotoxic due to apoptosis and necroptosis. Normally, these cytotoxic reaction routes are inhibited, but under some pathophysiological circumstances, TNF can also provoke cell death in addition to inflammatory signalization. These cell death processes release DAMPs (damage-associated molecular pattern molecules), which can contribute to inflammation and tissue damage. This renewed attention to TNF as a cytotoxic molecule is aligned with the way TNF research began some 40-odd years ago, as the “tumor necrosis factor”.

How has this one molecule managed to fascinate you all for 30 years?
Claude: That’s not difficult with a molecule such as TNF, which is involved in virtually all biological
processes.

Rudi: When I started, TNF was only studied because of its cytotoxic activity on tumor cells, and TNF signal transduction was limited to a linear sequence of a few proteins. Now we know that TNF is a pleiotropic molecule and TNF signal transduction is a complex network of hundreds of proteins. How these molecules communicate – and perhaps even more importantly, how the strength and duration of the TNF signal is determined – is still largely a mystery. So there are still plenty of challenges left! 

          “Walter Fiers was essential in the research of TNF 
           immediately after its discovery”

                 Claude Libert

Peter: What fascinates me is how one molecule with only two types of receptors (TNFR1 and TNFR2) can provoke so many biological activities. Insight into this is progressing and continuously creating a new context for interpreting findings and formulating new objectives.

Are you seeing an evolution in TNF research?
Claude: Over the years, the broad strokes have become clearer; now we are zooming in on the details, which could make the difference between good and bad medication. TNF research was previously only conducted by immunologists, but now it’s done more by molecular biologists.

Rudi: I am also seeing a major evolution towards research of the mechanisms that determine the
dynamics of the signals and the cross-talk between various signaling pathways.

Peter: In addition to the intracellular aspects, the intercellular processes are once again receiving
a lot of attention. Cell death not only promotes inflammation but can also initiate tissue regeneration through phagocytosis of dead or damaged cells. Better knowledge of these regeneration processes can result in strategies that can strengthen the restorative power of our body.

What do you expect from the next 10 to 40 years of TNF research?
Claude: I think that improved TNF inhibitors are imminent. In order to bring down costs, there will be a need for small molecule drugs that inhibit TNFR1 or TNFR2.

Rudi: Research into signal transduction will focus, among other things, on the role of post-translational modifications of signaling molecules and the enzymes that are involved in this. The knowledge gained from this will undoubtedly result in new targets for improved and more specific therapeutics. Given the side effects and the high production costs of the current anti-TNF therapeutics, there is certainly a need for this.

Peter: Biologicals are important, but let’s not forget that specific drugs based on detailed insights into signal transduction pathways in cell death and inflammation are yielding very good results in various experimental disease models. It is also becoming clear that combined targeting of various proteins frequently yields spectacular results. The pharmaceutical industry has traditionally often promoted “single” targeting in inflammatory diseases and cancer for regulatory and IP-strategic reasons. However, biology does not work through single signals, but rather through hubs and networks. And these require multifactorial targeting. The TNF research makes this very clear.

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