Cytokine Testing in Clinical Pain Practice
If you attended medical school more than twenty years ago, you may be unfamiliar with the significance of cytokines in modern medicine. As an example of current interest in the topic, there are almost five million hits on this subject on Google and 419,000 on Pubmed. Reviewing the type of work being reported, the nature of the first problem with cytokines is immediately evident as far as the clinician is concerned. The great majority of the work is pure research, complex and often relates to animal models. To say it is esoteric is an understatement; the human research frequently relates to end-stage diseases and tropical medicine. There are virtually no papers on the utility of cytokine measurement in traditional clinical medicine—the variety of medicine practiced in every hospital and medical clinic in America. This paper will suggest the use of cytokine testing as a screening tool—something like a sedimentation rate but better.
Nearly every subspecialty of medicine is represented in the work being done on cytokines. Certainly the most studies might be encountered in rheumatology, but they may be seen in the fields of immunology, neurology, headache and pain medicine, internal medicine, dentistry, dermatology, oncology, and many others.
Cytokines are a type of signaling molecules and are important in the intercommunication between body cells.1,2 They are most often discussed in the context of immune response, but are also significant factors in the genesis of autoimmune disorders. They may be proteins, peptides or glycoproteins, and can be produced by a diverse population of cells and affect a number of different target cells. They differ from hormones in that they are not produced by a single organ, nor are they likely to have a narrow target range.
There is a dizzying array of these substances discussed in the literature, with subsets being divided into six basic categories. These include interleukins (of which there are at least 18 varieties and are produced by leucocytes or macro-phages and act on other leucocytes), chemokines (which are important in attracting immunologically active cells to an area and of which there are at least 24), colony stimulating factors, interferons, tumor necrosis factor subtypes, and growth factors. Unfortunately, the sheer number of—and the variable terminology used to name them—increases the confusion of this important topic.
The simplest way to explain cytokines is to say that their measured presence suggests the human body is reacting to something; they reflect trouble, some kind of threat, injury or specific infection. Since cytokines are not specific in themselves, they don’t make diagnoses, but rather become evidence in favor of diagnoses in conjunction with other evidence. They are circumstancial evidence so a history, physical and other testing are still required.
We have been employing a panel of twelve cytokines, performed by ARUP laboratory in Salt Lake City who do a multiplexed fluorescent microsphere immuno-assay (Luminex Corp).3 These cover many of the cytokines most commonly men-tioned in the literature when reviewing the topic. Many others could be tested individually and other panels at other labs could be substituted, but we elected to use one well-recognized and well-qualified laboratory. ARUP Laboratories, owned by the University of Utah, is a national clinical and anatomic pathology reference laboratory engaged in research and development with an extensive test menu of highly complex and unique medical tests.Even doing this, it required several months to educate our local laboratory facilities to handle the tests correctly. We have also asked our patients to use only one lab when doing these tests to avoid confusion, mistakes and frequent phone calls to our office. For example, the sample must arrive frozen at ARUP or the whole process starts over again.
Summary of Twelve Basic Cytokines (ADA interleukins or IL’s)4-6
A discussion of normal levels of cytokine in serum (as determined by ARUP Laboratories) is presented below and summarized in Table 1.
Tumor Necrosis Factor Alpha (TNF-alpha). The presence of TNF-alpha was first suggested in 1968. The agent discovered was termed lymphotoxin. In 1975, it was renamed as TNF-alpha. It has numerous actions on various organ systems and often in association with other cytokines. It functions as an acute phase responder in the immune system and may effect many other organ systems as well. It causes local inflammation by attracting neutrophils. Beyond the utility of tumor necrosis factor in the immune system, the substance may produce other problems. With acute high dose exposure of TNF-alpha, there may be shock and tissue damage, gastrointestinal necrosis, catabolic hormone release, vascular leakage syndrome, adult respiratory distress disorder and death. With chronic exposure there can be weight loss, anorexia, protein catabolism, lipid depletion and hepatosplenomegally. This substance has been correlated with numerous disease processes, most often autoimmune disorders such as rheumatoid arthritis, AIDS, ankylosing spondylitis, psoriasis, and Chrohn’s disease. One problem with TNF-alpha testing is that it may only appear in serum or spinal fluid for a very short period of time at the onset of an illness and immune response and, therefore, would be missed on later testing. Average serum level of TNF-alpha in normal subjects (as determined by ARUP Labs) is 1.3pg/ml
IL-1 and IL-1b. Produced by a variety of cells including NK and B cells. They cause growth and proliferation of immunological cells and may cause inflammation and may lead to fever. IL-1b is the one tested in the routine panel. An increased level of IL-1b has been seen in RA, sepsis, cachexia, leukemia, inflammatory bowel disease, AIDS, and transplant reactions. Higher levels have been associated with an increased risk of myocardial infarction (MI). ARUP lists IL-1b as normal at 0-36 pg/ml. In a recent study of 109 normal subjects, they found an average serum level of 13.5 pg/ml.
IL-2. Produced by thymus cells, IL-2 will cause activation and growth of immunological cells. It has been used as a cancer treatment. The ARUP average blood level is 1.6 pg/ml.
IL-2r. This is a reflection of the IL-2 receptor and is released into circulation under a variety of circumstances. The best known correlation is with organ transplant rejection, but there is also considerable interest in IL-2r associated with lymphoma, Hodgkins disease and leukemia. Otherwise, it may be noted in a great variety of autoimmune disorders, nephropathy and renal failure. The ARUP average level is 502 pg/ml.
IL-3. This is not a routine member of the cytokine panel. It is a cytokine produced by leukocytes and other cells in the body and increases the number of blood cells being made by the marrow. It can be used as a form of cancer therapy to boost the immune system in cancer therapy.
IL-4. This cytokine is produced by leukocytes and other body cells and causes B and T lymphocytes to increase in number and produce antibodies. IL-4 produced in the laboratory can be used as a form of cancer therapy. The ARUP average level in serum is 0.1.