Can Fatigue and Cytokines Be Markers of A Chronic Illness?

Fatigue is among the earliest and common symptoms of an illness. In fact, most patients complain about fatigue at the time of hospital admission. Fatigue can be associated with various health problems, such as anemia, hyperthyroidism, electrolyte imbalance, diabetes, depression, sleep problems, viral infection, inflammatory illness (rheumatoid arthritis and psoriatic arthritis), cancers, autoimmune diseases, or Parkinson’s disease.

What is Fatigue?

Fatigue is an extreme tiredness causing you to be unable to finish your daily activities, work and function normally in family and social roles.

There are three dimensions of fatigue:

• The physical fatigue: you feel too tired and weak to do physical activities.
• The motivational fatigue: you lose your motivation to start activities.
• The cognitive fatigue: it’s difficult for you to concentrate during complex activities and finish those activities.

Why Does Fatigue Matter?

Fatigue is different from the tiredness experienced after a long exercise or sleep deprivation. With tiredness, you feel energized to resume your daily activities after you sleep. But fatigue is more weakening and persistent throughout the day than tiredness. In addition, fatigue tends to be more disruptive to your daily life, your relationship with your loved ones, and social life.

Every morning you wonder what makes you feel tired even after having eight hours of sleep. Even if you manage to leave the bed, the urge to lie down fills your mind as soon as you finish your breakfast. After resting, you still feel the same level of tiredness. It’s hard for you to focus on finishing your work and your whole body feel heavy. You lose your motivation to do your daily routines. Because of your fatigue, you keep canceling your appointment with your family and you even skip exercising.

As the time goes by, your fatigue becomes a part of your daily battle. Before you realize, it’s been more than a month. Fatigue may seem like something you can ignore, but it could be a sign of an illness.

Fatigue and Cytokines

Fatigue is one of the symptoms many people feel when they have chronic illness. Other ‘sickness behavior’ includes muscle weakness, sleepiness, fever, and loss of appetite. Sickness behavior is a response against pathogens for adaptation and survival of people and animals. During this response, we prioritize our energy, spending it more on fighting infections rather than other activities such as foraging for food. Furthermore, this sickness behavior creates a self-isolation and prevents the spread of a disease among ourselves.

When our body fights an infection, there is an increase of cytokine activity. Cytokines are proteins involved in cell signaling. They allow cells to communicate with other cells. These cytokines play important biological roles, such as immune responses, inflammation, cell growth or cell death. In addition to performing their physiological functions, some cytokines are also associated with sickness behavior.

The Inflammatory Response by the Release of Cytokines (Slaats et al. 2016). Pathogens trigger the binding of pathogen-associated molecular patterns (PAMPs) to their receptors on immune cells, such as macrophages. Those molecules further activate inflammatory and immune responses on other tissues or immune cells by the activation of cytokines (including TNF alpha, IL-1B, and IL-6).

Below are some examples of cytokines with their biological functions:

IL-6

Human IL6 protein structure. Homology model of the human IL6 protein is created with SWISS-MODEL ( https://swissmodel.expasy.org).

Functions:

• Involved in the immune system and inflammatory responses.
• Supports the survival of several types of neurons in the central nervous system.
• Delays the progression of neurodegeneration by increasing the number of surviving neurons.
• Acts as a growth factor of some malignant tumors.

IL-1B

Human IL-1B protein structure. Homology model of the human IL-1B protein is created with SWISS-MODEL (https://swissmodel.expasy.org).

Functions:

• Activates responses against infection, injury and immune challenge.
• Involved during inflammatory responses.
• Involved in neurodegeneration.

TNF alpha

Human TNF alpha protein structure. Homology model of the human TNF alpha protein is created with SWISS-MODEL (https://swissmodel.expasy.org).

Functions:

• Mediates inflammatory responses caused by injury and infection.
• Acts as a component of cell death usually in cancer cells or infected cells.
• Involved in activation of immune response.
• Involved in neurodegeneration.

Fatigue in Parkinson’s Disease, Cancers, and Rheumatoid Arthritis

Some studies have reported the correlation between fatigue and the level of particular cytokines in some illness.

Parkinson’s Disease

Most patients with Parkinson’s disease often describe fatigue as one of their incapacitating symptoms. Fatigue can also affect newly diagnosed patients with minimal motor symptoms (such as tremor). Fatigue in Parkinson’s disease patients often persists and gets worse over time.

Cytokines associated with fatigue in Parkinson’s disease:

• In blood serum of newly diagnosed Parkinson’s disease, patients with fatigue, higher levels of cytokines IL-6, IL1-Ra, sIL-2R, and VCAM-are detected.
• Many cytokines, including TNF alpha, IL1-B, IL-6, IL-2, IFNG, TGF alpha and TGF B1, are upregulated in the brain of patients with Parkinson’s disease.
• Research suggested the use of IL-6, TNF alpha and VCAM-1 cytokines as potential markers in blood plasma, in addition to other markers, to separate patients with Parkinson’s disease from patients with other neurodegenerative diseases.

Cancers

Patients diagnosed with cancers may describe fatigue as unpleasant, chronic, and incapacitating throughout the day. In addition to fatigue, they may also experience pain, depression, and other symptoms.

Cytokines associated with fatigue in cancers:

• Newly diagnosed patients with acute myelogenous leukemia have high levels of IL-6, IL-1 RA, and TNF alpha associated with fatigue. Before surgery, many patients with ovarian cancer, who experience fatigue, have high level of IL-6.However, there is no increase of the level of IL-6 in breast cancer patients with fatigue before surgery.
• During chemotherapy, IL-6 level increases in the serum of many patients with breast cancer who experience fatigue.
• Although most of cancer survivors experience no fatigue post treatment, 20-30% of cancer survivors still experience fatigue. Among breast cancer survivors with fatigue, the level of some circulating cytokines (including IL1-1RA, sTNF-RII and soluble IL-6 receptor) in the serum increase when compared to breast cancer survivors without fatigue. Expression levels of some marker genes in leukocytes, such as il-1b and il-6, increases for some breast cancer survivors with persistent fatigue. In ovarian cancer survivors, a decrease of IL-6 is associated with a decrease of fatigue in the year after treatment.

Rheumatoid Arthritis

In most clinical studies, patients with inflammatory rheumatic disorders experience the three dimensions of fatigue (physical, motivation, and cognitive fatigue), in addition to pain and other symptoms.

Cytokines associated with fatigue in rheumatoid arthritis:

• Fatigue is common in most of patients diagnosed with rheumatoid arthritis. Many patients with inflammatory rheumatoid disorders also have an increased level of cytokines, including IL-1, TNF alpha, IL-23 and IL-17. However, many studies investigated a correlation between fatigue and the level of many of these cytokines have found inconsistencies in the results.
• The level of fatigue increases as the level of IL-6 increases in the serum of patients with rheumatoid arthritis compared to healthy controls.

Using Anti-Inflammatory Agents to Target Cytokines

There are two possible approaches for treating inflammation in inflammatory illness. One is by using monoclonal antibody therapy and the other is by developing peptide drugs. Peptide drugs usually have a higher specificity than antibodies. These drugs act by binding to the target molecule or cell surface receptors, therefore blocking inflammatory response.

Below are examples of anti-inflammatory therapy to block the activity of cytokines:

TNF alpha Inhibitor Therapy

A therapeutic agent, such as TNF inhibitor therapy, has led to a small reduction of fatigue and a decrease in pain for patients with rheumatoid arthritis and psoriatic arthritis. The use of the TNF alpha inhibitor has been effective in patients with rheumatoid arthritis.

The Mode of Action of TNF Inhibitors (Scott et al. 2013). TNF Inhibitors bind to TNF alpha and blocks inflammatory response. The first type of TNF alpha inhibitor is a recombinant protein that consists of the TNF alpha-receptor linked to the Fc portion of human antibody. The second type is an anti-TNF alpha antibody. On the target cells, the TNF alpha inhibitor binds to TNF alpha to prevent the interactions between TNF alpha-receptors and TNF alpha.

An anti-inflammatory peptide KC-18

In 2019, Jiang et al. developed an anti-inflammatory agent, KC18, to bind the recombinant proteins of IL-6, IL-1B, and TNF alpha.KC-18 is a peptide derived from the receptors of those three cytokines. Their result suggested KC-18 reduced the binding of those cytokines into their receptors. Unfortunately, this anti-inflammatory agent hasn’t been tested in clinical studies. However, this study could provide a strategy to develop anti-inflammatory peptide drugs in the future.

When you experience fatigue with other sickness symptoms (such as pain) for a long time, your body is most likely trying to tell you to pay attention to your health. You may want to consider calling your doctor and consulting them about your symptoms. It’s the only way to make sure that it is not an underlying illness.

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