Fibromyalgia and IL-17
Interleukin-17 and the T helper (Th)-17 cells play a key role in tissue inflammation and host defence and, recently, the Th17-pathway has been implicated in numerous inflammatory and autoimmune diseases.
The concept that FM is an inflammatory state is not generally accepted. However, a recent systematic review of 25 selected articles reveals that FM patients have high serum levels of IL-1 receptor antagonist, IL-6 and IL-8 (Uçeyler N et al., BMC Musculoskelet Disord, 2011, 12:24).
In the study by Andrei Pernambuco and colleagues from the Federal University of Minas Gerais, Belo Horizonte, MG, Brazil investigated 58 women with FM, diagnosed according to the he American College of Rheumatology (ACR criteria. The study group included only patients with primary fibromyalgia.
Patients diagnosed with FM with a history or presence of: chronic inflammatory conditions, autoimmune diseases, psychiatric disorders and or presenting infectious were excluded from the study. Also excluded were patients who had used anti-inflammatory drugs in the past six months, pregnant patients or women who were breastfeeding. Cytokine levels were assessed using a commercial BDTM Cytometric Bead Array (CBA) TH1/TH2/TH17 cytokine kit (BD Bioscience, San Diego, CA, USA).
The authors report that the levels of IL-17A were significantly higher in FM patients when compared to healthy controls. The levels of IL-2, TNF, IFNγ and IL-4 were also significantly higher in FM patients; No significant difference was observed in IL-10 and neither in IL-6 levels.
Of note, high plasma levels of IL-17 correlated positively with the levels of IL-2, TNF and IFN-γ, thus suggesting the involvement of inflammatory mechanisms in the development of this syndrome.
Interestingly, according to the authors, previous research, in other clinical conditions, indicates that IL-17A positively correlates with indices of pain, depression and anxiety, which are symptoms frequently reported by patients with FM.
The study may provide some new insights into the pathogenesis of FM, and may suggest an anti-inflammatory approach and/or new therapeutic target(s) for this common condition and syndrome.
Source: Clin Exp Rheumatol. 2013 Nov-Dec;31(6 Suppl 79):S60-3. Epub 2013 Sep 10.
Read more: Clin Exp Rheumatol
As we reported previously, a study published in Molecular Medicine Reports provides further evidence that IL-17 contributes to neuropathic pain through the activation of astrocytes and secretion of proinflammatory cytokines. These observations were associated with an up-regulation of IL‑17, IL‑1β and IL‑6 mRNA expression and high IL-17 protein levels in the spinal cord.
Intrathecal injection of recombinant IL-17 promotes thermal hyperalgesia of normal mice, which demonstrates that central IL-17 is a key factor in inflammatory pain. Of note, IL-17A generates hyperexcitability of small to medium-sized dorsal root ganglion (DRG) neurons, implicating regulation of voltage-gated ion channels, and appears to include upregulated sensitivity of TRPV4 ion channels.
Ernberg et al. from Sweden conducted one of the largest studies investigating circulating cytokine levels in FM compared to age- and gender-matched healthy controls. Baseline plasma cytokine levels and clinical data were analyzed in 125 women with FM and 130 age-matched healthy women. For the FM women, a diagnosis of FM according to the ACR-1990 classification criteria was also required.
Exclusion criteria for both groups were (1) high blood pressure, (2) osteoarthritis in the hip or knee, (3) other severe somatic or psychiatric disorders, (4) primary causes of pain other than FM, (5) high consumption of alcohol, (6) participation in a rehabilitation program within the past year, (7) regular resistance exercise or relaxation therapy twice a week or more, (8) inability to understand or speak Swedish, and (9) not being able to refrain from analgesics, NSAID, or hypnotics for 48 hours prior to examinations.
It has been suggested by several researchers that chronic low-grade systemic inflammation may underlie the pathophysiology in chronic generalized pain conditions, such as FM.
Using multiplex panels analyzing 13 cytokines and chemokines, the univariate analyses showed increased levels of the proinflammatory IL-2, IL-6, TNF-α, IP-10, and eotaxin. The multivariate analysis—also considering the intercorrelation pattern between cytokines—revealed a slightly different pattern with IL-2, IL-6, IL-1β, eotaxin, and IL-17A being the most important cytokines that differentiated FM from controls.
Of note, Marzia Dolcino et al. from University of Verona, Italy, for the first time provided a comprehensive analysis of the transcriptome and interactome in FM patients. Importantly, their results indicate an autoimmune component in the pathogenesis of the disease, since FM gene expression profiles were characterized by a dual gene signatures (Th-17 and Type I interferon); and the combined presence of these two signatures is typical of autoimmune diseases.
Of note are the higher levels of circulant IL-17 producing CD4+ T cells and of serum cytokines such as TGF-beta, IL-6, IL-21 and IL-23 that promote Th17 differentiation survival and expansion in FM patients, thus confirming the gene signature and the presence of an ongoing inflammatory process.
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