I want to summarize some research I conducted recently on a study that evaluated inflammatory cytokines in women with IC with and without Hunner’s Ulcers to see if this non-invasive test could be used to substitute the current method of evaluation which is a very invasive and painful cystoscopy. First I am going to review what a cytokine is, and then briefly summarize my findings.
What is a Cytokine Anyway?
Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. They are signaling molecules that aid cell to cell communication in immune response and stimulate the movement of cells towards the site of inflammation, infection or trauma (Mandal, n.d.). The word cytokine is a general name, but other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes) (Zhang & An, 2007). Cytokines have autocrine (by acting on cells that secrete them), paracrine (acting on nearby cells) and endocrine action (acting on distant cells). We have both pro-inflammatory and anti-inflammatory cytokines. “There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating nociceptive sensory neurons” (Zhang & An, 2007). Cytokines are made by many different cell population, but the majority of them are produced by helper T cells (Th) and macrophages. Cytokines can be recruited by macrophages, mast cells, endothelial cells and Schwann cells.
The Role of Cytokines in Inflammation:
Pro-inflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. The main pro-inflammatory cytokines are IL-1B, IL-6 and TNF-a. These are often involved in the process of pathological pain. “There is evidence that pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and chemokines (e.g., MCP-1) may directly modulate neuronal activity in various classes of neurons in the peripheral and central nervous system” (Zhang & An, 2007)
- IL-B-This cytokine is released mostly by monocytes and macrophages as well as nonimmune cells (fibroblasts and endothelial cells) during cell injury, infection, inflammation and invasion. IL-B was found tin increase the production of substance P and prstoaglandin E2 in a number of neuronal and glial cells (Zhang & An, 2007)
- IL-6 Plays a key role in the neuronal reaction to nerve injury, and the development of neuropathic pain behavior following a peripheral nerve injury. IN fact, suppression of IL-6 has been demonstrated to lead to reduced regenerative effects
- TNF-a-This is also known as a cachectin, in an inflammatory cytokine that plays a key role in pain models. “TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs)” (Zhang & An, 2007). It has been show to play an important role in both inflammatory and neuropathic hyperalgesia (increased sensitivity to pain).
Anti-inflammatory cytokines are a series of immunoregulatory molecules that control the pro-inflammatory cytokine response. “Cytokines act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response” (Zhang & An, 2007). Major anti-inflammatory cytokines include IL-1 receptor antagonist, IL-4, IL-10, IL-11 and IL-13. Leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF)-β are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances. Specific cytokine receptors for IL-1, TNF-α, and IL-18 also function as inhibitors for pro-inflammatory cytokines (Zhang & An, 2007).
IL-10 has to most potent anti-inflammatory properties, being able to repress the expression of inflammatory cytokines such as TNF-α, IL-6 and IL-1 by activated macrophages (Zhang & An, 2007). “Recent clinical studies also indicate that low blood levels of IL-10 and another anti-inflammatory cytokine, IL-4, could be key to chronic pain since low concentrations of these two cytokines were found in patients with chronic widespread pain” (Zhang & An, 2007).
What I found interesting:
There is debate among experts over whether certain molecules should be called hormones or cytokines, which I found particularly interesting. Cytokines differ in classic proteins in that the concentrations of cytokines can increase in magnitude of almost a thousand-fold in response to an infection or inflammation, which is unlike proteins that do not differ in circulation by more than one order of magnitude (Mandal, n.d.). Additionally, cytokines have a much larger distribution of sources for their production since nearly all cells with a nucleus has the ability to produce them, particularly IL-1, IL-6, and TNF-a. These include endothelial cells, epithelial cells and resident macrophages (Mandal, n.d.). The classic hormones, however, are secreted from distant glands, as is seen in the secretion of insulin from the pancreas. Additionally, cytokines can exert both systemic and local effects on the body, unlike hormones. “A cytokine’s actions may affect the same cell it was secreted from, other cells nearby or may act in a more endocrine manner and produce effects across the whole of the body, such as in the case with fever, for example” (Mandal, n.d.) Cytokines are often redundant in their activity, which means similar functions can be stimulated by different cytokines (Zhang & An, 2007). They are often produced in a cascade, stimulating the production of additional cytokines, and can act both synergistically or antagonistically (Zhang & An, 2007).
Development of Interstitial Cystitis (IC) Risk Score for Bladder Permeability
I picked IC because this is an area of interest for me since I have been afflicted with this illness and work to support other women who are also dealing with the pain of IC. IC is a painful bladder syndrome that is multifactorial consisting of severe pelvic and genitalia pain, as well as dysfunctional urination. The disease is characterized by urinary frequency, urgency and severe pelvic pain. IC can compromise sexual function, employment and quality of life (Lamb, Janicki, Bartolone, Peters, & Chancellor, 2017). A percentage of patients also present with Hunner’s lesions or ulcers on their bladder walls (UIC), which is diagnosed by cystoscopy, a rather painful procedure. The objective of this study was to determine if a calculated Bladder Permeability Defect Risk Score (BP-RS) based on non-invasive urinary cytokines could discriminate UIC patients from controls and IC patients without Hunner’s ulcers. If successful, this may be used as a less invasive way to diagnose IC with UIC instead of the painful cystoscopy.
Pro-inflammatory cytokines such as IL-6 and IL-8 have been reported to be increased in IC patients and has been positively associated with pain scores (Lamb et al., 2017). The study measured the expression of cytokines, chemokines and growth factors in urine samples of patients recruited for the study. For the validation set and a portion of the training set, only GRO, IL-6, IL-8, and MCP-1 were measured. In the study, 448 patients (96.1% women), 54 patients had IC with Hunner’s lesions and 394 had either no IC or IC without Hunner’s lesions.
These findings are consistent with previous characteristics of IC patients with and without the Hunner’s ulcers. IC with Hunner’s lesions may have a more bladder-centric involvement whereas IC without Hunner’s lesions may be more systemic. “Patients with NUIC can have other comorbid pain syndromes, such as pelvic floor dysfunction, and respond better to systemic therapy” (Lamb et al., 2017). In contrast, UIC respond to more localized therapy focused on the bladder when demonstrating the pathology consists of urothelial permeability defect. “As such, UIC and NUIC may have different disease etiologies and therefore differential biomarkers may be feasible” (Lamb et al., 2017).
L-8 contributed most significantly toward the predictions (48%), followed by GRO (33%) and IL-6 (19%).IL-6 also is a pro-inflammatory cytokine and has been previously reported to be elevated in IC, and may be reflective of general inflammation. Additionally, although several groups have investigated the expression of IL-8 in IC, GRO has been less studied. It has also been reported to be increased in other urological disease, such as bacterial cystitis and bladder cancer. This study also is a step forward in evaluating alternative methods of diagnosing IC that is less invasive, damaging and painful than the current methods available.
Lamb, L. E., Janicki, J. J., Bartolone, S. N., Peters, K. M., & Chancellor, M. B. (2017). Development of an interstitial cystitis risk score for bladder permeability. PLoS ONE, 12(10), e0185686. doi:10.1371/journal.pone.0185686
Mandal, Ananya. (n.d.)What are Cytokines? Retrieved 2018, April 30 from https://www.news-medical.net/health/What-are-Cytokines.aspx
Zhang, J. M., & An, J. (2007). Cytokines, inflammation, and pain. Int Anesthesiol Clin, 45(2), 27-37. doi:10.1097/AIA.0b013e318034194e