Or, Cyto-What?

     Cytokines are small molecules that do not stay around very long in the body before they are either taken up or degraded. They act as chemical messengers to affect immune responses, tissue repair, or cell growth.  Their production is influenced by both the central nervous system and the immune system. The sympathetic nervous system, through the secretion of catecholamines, will activate the hypothalamic-pituitary-adrenal axis (HPA) and stimulate the release of cytokines. If you don’t know about HPA axis then read the two short reports on “The Neuroendocrine Theories Behind Fibromyalgia.” Catecholamines are the “fight or flight” hormones produced by the adrenal glands – epinephrine and norepinephrine and they primarily act through the sympathetic nervous system. For more information about epinephrine and norepinephrine you can read the short reports on “Dysautonomia, ”and the two-part series on ‘The Neuroendocrine Theories of Fibromyalgia.”

     The most common cytokines are “interleukins,” and they are abbreviated and numbered, e.g. IL-1, IL-6, IL-8, and so on. IL-8 is a key cytokine that plays a role in inflammation. It is released by macrophages, cells that are activated in response to tissue injury.  They help promote pain in laboratory animals and will cause pain in a dose dependent manner, meaning the higher the concentration of IL-8, the greater the pain the animal will experience.  The secretion of IL-8 by macrophages can also be induced by substance P, which is a major nerve transmitter that you will read quite a bit about in the sections on pain in fibromyalgia syndrome (FMS) that are coming up in the near future. IL-8 is of particular importance because it also activates the sympathetic nervous system. IL-6 and another cytokine called tumor necrosis factor-alpha (TNF-alpha) are also major inflammatory cytokines and have been implicated in the generation of a particular type of pain called neuropathic pain.

     A group of researchers  first proposed a link between cytokines and FMS when they observed that patients given IL-2 cell therapy for melanoma or terminal renal cell carcinoma developed FMS-like symptoms such as myalgia, cognitive impairment, and tender points. The IL-2 therapy was part of the treatment for these cancers. Since that time, there have been numerous studies that have attempted to correlate the role of cytokines to clinical manifestations of FMS based, in part, between their relationships with the HPA axis and the sympathetic nervous system. If you haven’t done so, it’s definitely time to read the two part series on the “Neuroendocrine Theories Behind Fibromyalgia.”

     Part of the interest is driven by what is known by psychiatrists as the “sickness behaviour” noted in FMS – pain, fatigue, cognitive changes, and depression that tends to match those signs seen with activation of the immune response system as a result of an infection. Remember, people with FMS will tend to say they feel like they have the “flu” all the time, that’s been one of the best ways used to describe FMS to other people. Psychiatrists are doctors, they like to have more medical ways to say things, so they called that common way of expressing FMS, “sickness behaviour.”

     Although patterns have tended to emerge, there are some subtle differences. The discordant results may reflect the small sample sizes used in the studies, differences in patients’ conditions, the amount of adipose tissue (which affect how cytokines are produced), as well as dissimilarities in laboratory techniques; no two studies were exactly alike.

     If you’re ready – here’s a rundown on what’s been found so far (take a deep breath).  One group of researchers have published two studies that found significantly elevated levels of IL-8 that correlated to pain intensity as measured by tender points.  Another group has also found high levels of IL-8 in FMS patients, but not IL-10 or TNF-alpha. On the other hand, different researchers noted high levels of IL-8 as well as IL-10 and TNF-alpha.  Then some other folks found elevated IL-8 and TNF-alpha but not IL-10. Wait a minute, here’s a group that reported no differences in IL-10 or TNF-alpha but now this fellow found decreased levels of TNF-alpha.  Another common inflammatory cytokine, IL-6, was not found to be higher in four studies of FMS patients, including a major report from the National Institute of Health, although a major FMS researcher group noted higher levels in patients, provided they had symptoms for more than two years. Confused? So is everyone else.

     This could be a reason - in a study of healthy adults a researcher found that after the application of an acute painful stimulus, pain catastrophizing was strongly related to IL-6 reactivity which means that emotional responses may influence cytokine responses. Here’s another reason - a 2010 study found higher levels of IL-6 and IL-8 in a group that showed a defective growth hormone response to heavy exercise. What are you thinking? That there are a lot of factors that influence cytokines? Well, you’re right.

     A group of researchers published in 2008 the first study that looked at cytokine levels in FMS patients while they were receiving 6 months of multidisciplinary pain therapy.  TNF-alpha and IL-8 at baseline were significantly higher compared to controls and both were reduced with therapy. Similar to earlier findings, IL-8 levels were correlated to pain intensity. Because of its design in following patients, this study also suggested that .3while TNF-alpha and IL-8 may contribute to contributing to FMS, neither could be the direct cause of FMS pain as it was only near the end of the study that levels correlated to pain intensity; both levels remained high earlier in the study while the patients reported their pain was decreasing.

     An often neglected effect of cytokines is their behavior manifestations, we mentioned this earlier – “sickness behavior.” These non-specific symptoms attributed to cytokines include weakness, malaise, concentration difficulties, anhedonia (generally feeling the ‘blues’), depression, and fatigue. People with FMS aren’t alone. These have been observed in people who have suffered a myocardial infarction and who also have diabetes, and cancer. Remember, they can also be brought on by therapy with cytokines. If you’re wondering why this would have ever been the case think about it from an evolutionary perspective.  Evolutionarily, this response would have been regarded as adaptive by promoting inactivity and rest but in chronic conditions these manifestations are now maladaptive, just like FMS is maladaptive.

     Cytokines are reflective of the general “state of the union” in someone who has FMS. They appear to contribute to the disease through a myriad of ways which manifest both in behaviour and physiologic characteristics. The good news is, they don’t seem to be a permanent fixture and as treatment progresses their influence becomes less and less.