Cytokines and Inflammation: Balance Required

Inflammation is bad, right? Chronic inflammation has been implicated in cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, cancer, autoimmune diseases, Alzheimer’s disease, other neurodegenerative disorders and more. Ad campaigns for new anti-inflammatory drugs are everywhere, and the best-selling over the counter pain relievers, taken by millions of people, work by suppressing inflammation. It is easy to get the impression that inflammation is always detrimental to health. But, without inflammation, all injuries would be permanent and our defenses against bacterial and viral invaders would be feeble. The inflammatory process is vital to life, the necessary first step in healing and in the body’s defense against infection.  But there is a dark side to this finely tuned system.  Inflammation can become chronic, outlasting the need for defense and repair, and damaging normal tissues in the process.

How inflammation works

Inflammation begins the when cells send out signals that they have been injured, by thermal or physical forces, or attacked, by organisms like bacteria or viruses. The language of this cellular communication is chemical, involving messenger molecules called cytokines (cyto meaning cell and kine, from kinos, meaning movement).  Cytokines attract of white blood cells to the area of injury, and they open pores in nearby tiny blood vessels to let in this defensive army, along with variety of specialized proteins that begin the job of healing.  Inflammation is the word used for the changes that occur in tissues as a result of the orderly events that ensue. With successful healing, signs of inflammation subside, and cellular cytokine production returns to the baseline level necessary for routine cellular maintenance and regeneration.

The normal course of healing inflammation

The cardinal signs of inflammation are redness, heat, swelling and pain. Redness, heat and swelling come from the increase in blood flow and permeability of the blood vessels. Pain is the result of cytokine stimulation of tiny nerve endings, and serves the purpose of limiting movement to limit further damage.  Some cytokine signals reach the temperature control centers in the brain, raising the body temperature to levels invading organisms tolerate poorly. Specialized immune cells immobilize and kill viruses and bacteria and cleanup cells called macrophages clear the debris. Gradually, dead and dying cells are walled off and disposed of. Rebuilding begins, taking advantage of scaffolding produced by the proteins which have leaked from the blood and caused clots to from. You see this process every time scab forms on a cut and later shrinks and peels away to reveal new skin cells beneath.

Maladaptive inflammation

But sometimes the inflammatory system does not gear back down, resulting in tissue damage rather than repair. This control failure may be rapid and catastrophic, the so-called cytokine storm, a term which has become familiar during the 2020 SARS-COV19 pandemic. It describes the damaging effects of an overreaction of the inflammatory response triggered by the immune system during infection or severe trauma. Oncoming cytokine storm cannot be predicted based on routine clinical parameters or tests, but researchers are beginning to tease out more sophisticated chemical markers of inflammation which correlate with more severe disease.

Maladaptive inflammation can also be slow and chronic, with progressive tissue damage like that which occurs in rheumatoid arthritis. The causes of such chronic inflammatory responses are legion and many don’t have obvious relationships to the normal inflammatory pathways. They include obesity, inactivity, toxic chemicals in food and the environment (xenobiotics), poor sleep, chronic infections and antibiotics that alter the normal bowel bacterial populations. Chronic inflammation is also a result of autoimmune responses to the body’s own tissues – cross reactions between immune responses to external agents and to the body’s cells, particularly in skin or joints and other organs like the thyroid gland. No one understands exactly why these self attacks begin to occur but autoimmunity is on the rise in all age groups.

Intertwined systems

The wide ranging influences on the inflammatory system reveals the deep connections between the body’s different physiologic systems. Disruption in one system influences production of chemical signalers in another. For instance, stress and lack of sleep suppress normal defenses against infections. External factors as simple as poor mechanical care of teeth allow chronic gum infections to take hold. Smoking and air pollution irritate the lungs. Lack of exercise changes the way blood flows though arteries, setting them up for damage and chronic inflammatory repair processes. And chronic use of anti-inflammatory drugs for aches and pains alters the finely tuned balance of cytokine signaling throughout the body. 

As we age, chronic inflammatory markers – measurements of some select cytokines like C-reactive protein – tend to rise. Attention to diet, exercise, sleep, dental care and stress management are within your control and help suppress inflammatory marker levels. Removal of allergens and irritating chemical triggers like smoke from the environment helps, as does attention to areas of the body that are sites of chronic infection, like teeth and skin.  

Pharmaceutical interventions are common ways of suppressing chronic inflammation. The NSAIDS, non-steroidal anti-inflammatory drugs like Advil, block cytokines called prostaglandins. Most recently, drugs-called biologicals target individual cytokines by blocking them with antibodies. The new biological drugs provide significant relief to people who suffer from autoimmune problems, but they can also impair the primary functions of defense and repair. Caution is required and risk-benefit calculations are necessary, because opportunistic infections – ones that the body normally handles well – can take hold and thrive. The body’s innate cancer surveillance system, which finds abnormal cells and induces their death before they become malignant, can also become less functional.  

Maintaining the Balance 

Cytokines and the inflammation they cause are part of an enormously complex, finely balanced cellular maintenance and body defense system. Small disruptions in the balance over time, such as happens with chronic use of anti-inflammatory drugs for treatment of pain, or chronic stimulation from infection, can show up in odd and seemingly unrelated ways, like an increased rate of heart attacks and strokes in chronic NSAID users and development of liver cancer in hepatitis sufferers. In an imperfect world, perfect balance is hard to maintain, but the inflammatory response system is far more often good than bad.    

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