The role of cytokines in disease was first explored in the 1970s, when an American study on macrophages indicated that they are capable of killing tumor cells. When macrophages (a type of white blood cell) are activated, they produce cytokines. These can then regulate immune response and fight tumor growth.
Related research projects confirmed that macrophage activation had a protective effect against malaria in mice. It was soon theorized that inflammatory proteins had roles both in promoting and fighting pathogens. By 1985, cytokines had become an important part of inflammation studies and disease research.
Today, proteomics and inflammation research are key ways to identify disease biomarkers and understand inflammation. In 2016, there were roughly 200 recognized cytokines, with more being identified all the time.
What Are Cytokines?
Cytokines are proteins that have a complex role in the body’s immune and inflammatory response. They oversee the interactions between immature blood cells, lymphoid cells, and inflammatory and anti-inflammatory cells.
In a perfect system, cytokines regulate these interactions to keep the body healthy. However, disruptions like over- or under-production of certain proteins can contribute to disease states.
Cytokines and Disease Progression
Chronic Inflammation
Many diseases are associated with an overactive inflammatory response. Cancers in particular can take advantage of inflammatory mechanisms to grow and spread. In prostate cancer, chronic inflammation can contribute to the genesis and development of the disease.
A subset of cytokines called chemokines are instrumental in prostate cancer’s metastasis and therapy resistance. The tumor microenvironment is able to synthesize pro-inflammatory chemokines to grow and spread.
Chemokines are also able to protect tumor cells from chemotherapy drugs. This limits the effectiveness of existing therapeutics. To successfully treat cancers, therapies need to be able to work around these tumor mechanisms and address tumor heterogeneity.
Inflammation research is leading to major developments in disease treatment. Learn more here →
Disease Heterogeneity
Some common diseases are actually heterogeneous disease groups, meaning they have different root causes and different genetic makeups. This can make targeted treatments less effective, since the genetics of the condition aren't uniform.
For example, colorectal cancer is actually a group of several cancers. In a 2018 study out of Poland, researchers analyzed the presence of key cytokines in right colonic, left colonic, and rectal cancers.
Results found vastly different cytokine types and concentrations in each subgroup of cancer. They also identified changes in Th2 response and Th1 immunity in right-sided colon cancer tumors. These abnormalities may indicate a negative prognosis. On a broader scale, they indicate the need for additional protein research in many cancer groups.
Recurrence Risk
Unusual pro-inflammatory activity can lead to increased risk of cancer recurrence in some people. In HER2-negative breast cancer, inflammation is associated with increased distance recurrence risk, when cancer reappears in different areas of the body.
Analysis of 249 serum samples identified proinflammatory interleukin IL-6 as a biomarker of increased distance recurrence risk. Identifying more biomarkers is an important step toward more effective recurrence monitoring.
A Cytokine Storm
Cytokine release syndrome and cytokine storm are systemic inflammatory responses. In these conditions, extreme immune response and an over-release of cytokines into the bloodstream lead to adverse inflammatory reactions.
In 2010, a cytokine storm was identified in an experimental cancer treatment for the first time. T cell therapy led to a serious negative reaction for patients with ERBB2 expressing tumors. The therapy led to respiratory distress and, ultimately, the death of the patient.
Cytokine storm is also a possible symptom during COVID-19 infection. It can be paired with pneumonia and organ failure. Researchers identified eight cytokines with elevated levels in COVID-19 serum samples. Tissue damage and inflammation in tissue samples predicted worse outcomes for impacted patients.
Understanding why certain diseases and treatments create this response is an important component of developing effective therapeutics.
Cytokine Therapeutic Research
Because cytokines play an important role in immune response, many researchers have begun to investigate manipulating cytokine actions for therapeutic purposes. Below are some of the most common ways cytokine research is being turned toward disease treatment.
Immune Response Regulation
Because cytokines play a part in the interactions of many types of cells, they are a strong target for regulating immune response to disease. Animal models have shown that a cytokine-regulating vaccine could be developed for rheumatoid arthritis. Such a vaccine would decrease the expression of inflammatory proteins while boosting regulatory cytokines. This would then restore balance to a patient’s immune response. Compared to existing therapeutic approaches, this option would be less damaging to the immune system.
Cytokine blockers have been considered as a treatment for many types of arthritis. They are also under consideration in inflammatory bowel disease and bone tissue repair. Blocking unwanted cell response in these situations is a key to improving treatment methods.
Changing Bodily Structures
Some diseases change the body at a structural level. Cytokines are sometimes investigated as a way to manipulate or reverse those changes.
In severe cases of asthma, the airway’s structure changes permanently, making it difficult to breathe. For years, Th2 cytokines have been implicated in the disease process. Recently, Th17 cytokines IL-17 and IL-22 have also been identified, although applications for treatment are still unclear.
New evidence indicates that therapeutic targeting of Th17 cytokines may be beneficial in patients with reversible airway remodeling.
Barriers to Cytokine Use in Disease Treatment
Experimental treatments have shown that cytokines are a promising drug target. However, their involvement in inflammation response can lead to unexpected side effects. When so many pieces of immune response are impacted by an experimental treatment, it can be hard to predict unintended consequences.
“Immuno-stimulant” cytokines once showed promise in treating HIV-positive people and cancer patients. By injecting these stimulating cytokines, researchers hoped to support the suppressed immune system. However, increased inflammatory response from IL-1, IL-2, and other cytokines led to abandonment of this therapeutic research.
With more knowledge about the role of proteins in disease states, targeted protein treatments will become possible. With more research, it will be possible to manage unintended side effects and understand the consequences of immune therapies.
