Major genes that affect inflammation: IL-6 (Interleukin-6) and TNF-α (Tumor Necrosis Factor-alpha) are key messengers (cytokines) involved in inflammation and immune response.Updated 2 years ago

Inflammation or chronic inflammation is a key driver of premature ageing but without inflammation we wouldn't survive.

inflammation is a bit like your body's own personal fire department. It's an essential part of your immune system's toolkit and it's what helps you heal when you're injured or fight off infections when you're sick. When a problem pops up, like a cut on your finger or a virus in your lungs, your body turns on the inflammation response. It sends in special cells and proteins (like IL-6 and TNF-α) to take care of the issue and start the healing process. It's a really effective system, but just like a fire hose, it's possible for it to get out of control. If your body's inflammation response is turned up too high or stays on for too long, it can end up causing damage instead of helping you heal. This is why it's so important for the body to maintain a balance in managing inflammation.

Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) are substances produced by our bodies, playing essential roles in our immune system. They act like messengers, sparking inflammation, which is a crucial defense mechanism against injury or infection. However, if they're produced in excessive amounts or at inappropriate times, they can cause harmful levels of inflammation and contribute to various health problems, including arthritis, cancer, and Alzheimer's disease [1][3].

Specifically, IL-6 is a versatile substance that coordinates immune responses and other reactions to injuries. When it's produced excessively, it can help cause diseases such as arthritis and certain cancers [1]. The gene that encodes IL-6 has a variant known as rs1800795, which can increase IL-6 production. As a result, people with this variant may have an amplified inflammatory response and a higher risk of certain inflammatory diseases [2].

Similarly, TNF-α is a substance that controls a variety of cellular activities, including inflammation. Like IL-6, it can contribute to disease development when it's produced excessively or inappropriately, leading to conditions like depression, Alzheimer's disease, and inflammatory bowel diseases [3]. There's a variant in the TNF-α gene, rs1800629, which is associated with increased TNF-α production. This variant can elevate disease risk, particularly for autoimmune and infectious diseases like arthritis, Crohn's disease, and severe malaria [4].

The evolutionary benefits of producing a stronger inflammatory reponse

The evolution of genetic variants associated with heightened inflammatory response, such as those found in the IL-6 and TNF-α genes, can be understood within the context of the environment and challenges faced by our ancestors.

Increased production of inflammatory mediators, like IL-6 and TNF-α, might have conferred survival advantages in certain circumstances. For instance, a robust inflammatory response can help to effectively control and eliminate infections. During human evolution, when infectious diseases were a major cause of mortality, genetic variants that amplified the body's ability to fight off infections could have been beneficial and thus favored by natural selection [5].

However, these same genetic variations might also contribute to excessive or chronic inflammation under conditions of modern life, leading to a higher risk of various inflammatory and autoimmune diseases. This concept is known as the "mismatch hypothesis" or "evolutionary discordance hypothesis", suggesting that our bodies are best adapted to the environment in which we evolved, and changes in that environment can lead to health issues [6].

Understanding how we respond allows us to adapt our environment appropriately.

Keeping inflammation in check

1. The antioxidants ie Catalase (CAT) and Superoxide Dismutase 2 (SOD2): These are like the body's cleanup crew. They go around mopping up harmful substances called reactive oxygen species (ROS), or "free radicals," that can damage our cells if left unchecked.

2. IL-6 and TNF-α: These are like the body's alarm system. When there's an infection or injury, they send out signals that kickstart the body's immune response. This includes inflammation, which is a bit like calling the fire department: it's helpful for dealing with immediate threats, but can cause damage if it goes on for too long.

Now, the cleanup crew and the alarm system need to work together to keep things running smoothly:

• If there's too much damage from ROS, CAT and SOD2 work to clean it up. By doing so, they help to keep the body's alarm system from going into overdrive and creating too much inflammation.

• On the other hand, if the body's alarm system (IL-6 and TNF-α) sends out signals for inflammation, this can lead to more ROS being produced. But our body is clever: these signals can also tell our cleanup crew (SOD2 in particular) to work harder, helping to keep things in balance.

In short, CAT and SOD2 help control the level of ROS, reducing potential damage and keeping inflammation in check. Meanwhile, IL-6 and TNF-α help coordinate the body's response to threats, but they also make sure our cleanup crew is ready to handle any extra ROS produced during this response. It's all about balance!

See our article on strategies to reduce these inflammatory messengers and the role of IL6 in exericse.

References:

1. 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 May;1813(5):878-88.

2. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998 Oct 15;102(7):1369-76.

3. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001 Feb 23;104(4):487-501.

4. Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998 Jun;112(3):451-6.