Cytokines and How They Work

Cytokines serve as molecular messengers between cells. Cytokines are proteins that are produced by cells. With regard to arthritis, cytokines regulate various inflammatory responses. Cytokines interact with cells of the immune system in order to regulate the body's response to disease and infection, as well as mediate normal cellular processes in the body.

Cytokines are diverse, meaning they are not all alike. Cytokines serve various functions in the body:

• colony stimulating factors (stimulate the production of blood cells)
• growth and differentiation factors (function primarily in the development, tissue maintenance, and repair)
• immunoregulatory and proinflammatory cytokines (e.g., interferons, interleukins, and TNF-alpha that function in the immune system)

While "cytokines" is an umbrella term that includes all kinds, there are more specific names given to cytokines based on either the type of cell that makes them or the action they have in the body:

• Lymphokines (made by lymphocytes)
• Monokines (made by monocytes)
• Chemokines (associated with chemotactic actions)
• Interleukins (made by one leukocyte but act on other leukocytes)

The immune system is complex—different types of immune cells and proteins do different jobs. Cytokines are among those proteins. Explaining how cytokines work is difficult. It's a lesson in cell physiology. But, to understand inflammation, you must understand the role that cytokines play.

Cytokines are released by cells into the circulation or directly into tissue. The cytokines locate target immune cells and interact with receptors on the target immune cells by binding to them. The interaction triggers or stimulates specific responses by the target cells.

Overproduction or inappropriate production of certain cytokines by the body can result in disease. For example, it has been found that interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are produced in excess in rheumatoid arthritis where they are involved in inflammation and tissue destruction.

Biologic drugs have been developed to inhibit IL-1 or TNF-alpha. Kineret (anakinra) was developed as a treatment for rheumatoid arthritis and works by inhibiting the binding of IL-1 to its receptor. TNF-alpha inhibitors (also called TNF blockers) bind TNF and prevent TNF from attaching to cell surface receptors. Enbrel (etanercept), Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), and Cimzia (certolizumab pegol) are TNF blockers. Actemra (tocilizumab) binds IL-6.

More biologic drugs are in development. Study results from a pivotal Phase 3 study of sarilumab (named SARIL-RA-TARGET), a human antibody against the IL-6 receptor, revealed the drug met both its primary endpoints of improvement in signs and symptoms of rheumatoid arthritis and improvements in physical function. Sarilumab binds with high affinity to the IL-6 receptor, blocking the binding of IL-6 and disrupting the cytokine-mediated inflammatory signaling. However, on October 31, 2016, the FDA rejected sarilumab based on deficiencies they discovered during an inspection of the manufacturing process. Once corrections are made, Regeneron and Sanofi intend to resubmit for approval in 2017. In the meantime, on February 1, 2017, Health Canada approved the drug under the name, Kevzara (sarilumab).

While cytokines seem like a complex subject, it is essential to understanding the inflammatory process which is at the core of inflammatory types of arthritis. We know that there are both proinflammatory cytokines and anti-inflammatory cytokines. The proinflammatory cytokines play a role in the development of inflammatory and neuropathic pain. The anti-inflammatory cytokines are actually inflammatory cytokine antagonists. There is evidence to suggest that chemokines are involved in initiating pain, as well as in the persistence of pain.