Tumour necrosis factor, or TNF, is a protein that functions as a signaling molecule within the immune system. It belongs to a family of proteins known as cytokines, which are chemical messengers that help coordinate the body’s response to perceived threats. Primarily produced by immune cells like macrophages, TNF helps initiate inflammation, a foundational process the body uses to respond to infection or injury.
The release of TNF helps direct immune cells to a site of injury or infection, beginning the process of healing and pathogen clearance. In a healthy immune system, this inflammatory response is a temporary and targeted action.
The Dual Function of TNF
The influence of TNF within the body is complex, producing both beneficial and harmful outcomes depending on the situation. Its effects are dictated by its concentration and the specific biological context. TNF carries out its functions by binding to two main receptors on cell surfaces, known as TNFR1 and TNFR2, which trigger different downstream pathways.
In its protective capacity, TNF is a component of the acute inflammatory response that helps the body fight off infections. It signals to other immune cells, recruiting them to the site of an infection. It can also induce apoptosis (programmed cell death) to eliminate infected or abnormal cells.
A different scenario unfolds when TNF is produced in excessive amounts or for prolonged periods. This chronic production leads to persistent inflammation that begins to cause damage to the body’s own tissues. This sustained inflammatory state is implicated in the development of various chronic diseases.
Role in Inflammatory and Autoimmune Diseases
The damaging effects of long-term inflammation driven by TNF are a direct cause of symptoms in several autoimmune disorders. In these conditions, the immune system mistakenly targets the body’s own tissues, and excessive TNF production perpetuates the attack.
In rheumatoid arthritis, high levels of TNF are found in the joints of affected individuals. The cytokine promotes inflammation in the synovial tissue, the lining of the joints, which leads to swelling, pain, and stiffness. Over time, this chronic inflammation contributes to the progressive destruction of cartilage and bone that characterizes the disease.
Psoriasis is another condition linked to elevated TNF levels, where the inflammation targets the skin. This results in the rapid overproduction of skin cells, leading to the formation of thick, scaly patches.
In inflammatory bowel disease (IBD), including conditions like Crohn’s disease, TNF drives persistent inflammation in the gastrointestinal tract. This leads to tissue damage and ulceration.
Connection to Cancer
The name “tumour necrosis factor” originates from its initial discovery, where it was observed to cause the death (necrosis) of tumour cells in laboratory experiments. When administered in high, localized concentrations, TNF can trigger cell death pathways in cancerous cells and destroy the blood vessels that supply tumours. Its application in treatment has been limited by toxicity when administered systemically.
The relationship between TNF and cancer is nuanced. While high doses can kill tumour cells, chronic, low-level inflammation caused by TNF can paradoxically promote tumour growth. This occurs because sustained inflammation can create a microenvironment that helps cancer cells thrive. TNF can also contribute to tumour progression by promoting angiogenesis, the formation of new blood vessels that supply tumours with oxygen and nutrients.
Therapeutic Targeting of TNF
Given the role of excessive TNF in driving autoimmune diseases, a class of drugs known as TNF inhibitors has been developed to counteract its effects. These are biologic drugs, often composed of monoclonal antibodies, which are proteins engineered to target specific factors. Their primary function is to neutralize TNF before it can bind to its receptors and trigger the inflammatory cascade.
Some inhibitors are monoclonal antibodies that bind to TNF, sequestering the cytokine. Another type is a fusion protein that acts like a “decoy” receptor, binding to TNF and rendering it inactive.
These therapies are used to manage a variety of conditions where chronic inflammation is a central feature, including rheumatoid arthritis, psoriatic arthritis, psoriasis, ankylosing spondylitis, and inflammatory bowel diseases. By controlling the inflammatory process, these drugs can alleviate symptoms, reduce tissue damage, and slow the progression of the disease. Administration is through self-injection or intravenous infusion.
Risks of TNF Inhibition
Blocking a component of the immune system like TNF comes with inherent risks. Because TNF is part of the body’s defense against pathogens, inhibiting its function can compromise the ability to mount an effective immune response to infections. This immunosuppressive effect is the most significant concern associated with TNF inhibitor therapy, leading to an increased susceptibility to various infections.
A particular concern is the reactivation of latent tuberculosis (TB). TNF is needed for the formation and maintenance of granulomas, which are structures the immune system builds to contain the Mycobacterium tuberculosis bacteria. When TNF is blocked, these granulomas can break down, allowing the dormant bacteria to escape and multiply. Patients are routinely screened for latent TB before starting TNF inhibitor therapy.
Beyond the increased risk of infection, other side effects can occur, such as a drug-induced lupus-like syndrome or rare neurological issues. The decision to use TNF inhibitors requires careful consideration, weighing the benefits of controlling a debilitating autoimmune disease against the potential risks of weakening the body’s natural defenses.