1. Introduction
Multiple sclerosis (MS) is defined as an immune-mediated inflammatory, neurodegenerative, and demyelinating disease that impacts the central nervous system (CNS) in young individuals
[1][2]. Approximately 1 to 2.5 million people (mostly women, with a female-to-male ratio of 2:1) around the world are affected by MS
[3]. A variety of genetic and environmental factors, including immune system dysregulation, central nerve demyelination
[4][5], vitamin D deficiency, Epstein–Barr virus, and smoking
[6], have been considered as possible etiologies of MS. Ultimately, the exact primary nature of MS pathogenesis remains unknown
[7][8]. Although there are controversies regarding the exact mechanism of disease initiation, it is well known that inflammation plays an important role in pathogenesis of the disease
[9]. Inflammation promotes neurodegeneration and demyelination, starting with plaque formation in the white matter and progressing to macrophage and T-cell aggregation in the peripheral blood circulation
[10][11]. As important players in inflammation, cytokines
[12] are proteins that are released from the bloodstream, the cerebrospinal fluid (CSF), or both, which modulate the maturation and function of immune cells
[13][14].
In contrast to healthy individuals, over-secretion of T helper 1 (Th1) and proinflammatory cytokines leads to imbalanced serum levels of tumor necrosis factor (TNF-α), interferon-gamma (IFN-γ), interleukin (IL)-1, IL-2, IL-12, IL-15, IL-6, chemokine (C–X–C motif) ligand 8 (CXCL8) and CXCL13, chemokine (C–C motif) ligand 20 (CCL20), T helper 2 (Th2) and anti-inflammatory cytokines IL-4, IL-5, IL-10, and IL-13 in MS patients
[7][15]. Adipokines such as leptin, a proinflammatory cytokine, and adiponectin, an anti-inflammatory mediator, are cytokines produced by adipose tissue, playing crucial roles in the progression and pathogenesis of MS
[16]. In addition, secretion of proinflammatory factors is increased and secretion of anti-inflammatory cytokines is decreased in MS, which may result in intensified demyelination
[7]. Recent studies demonstrated that CXCL8, TNF-α, IL-12p40, IL-15, and CXCL13 are enhanced in both CSF and blood in MS patients.
Moderate exercise had a positive impact on low-grade inflammatory markers such as IL-6 and leptin [17][18]. Exercise led to increased anti-inflammatory markers in the initial response, but a decrease was also reported following a period of regular activity [19][20][21]. Conversely, there have been no reported significant changes in IL-17, TNF-α, IFN-γ, and IL-10 after exercise [11][16][22][23]. Two studies indicated that drawing clear conclusions about the impact of training on cytokine (ILs and TNF-α) and adipokine (leptin) levels in MS patients is impossible, and that exercise had no effect on MS clinical manifestations of systemic inflammation [11][24].
2. Discussion
2.1. Proinflammatory Cytokines
Interleukin-6 is a myokine released when skeletal muscle contracts and nine studies reported no change in IL-6 levels after various exercises
[12][23][25][26][27][28][29]. The current review is in agreement with the findings of a previous large review
[30], which reported that seven trials from eight studies did not show a statistically significant difference in IL-6 levels after exercise. A possible explanation for the observed lack of IL-6 decrease in response to exercise may be that baseline IL-6 levels are not elevated in MS patients, as would be expected with MS pathogenesis as an inflammatory disease. This hypothesis is supported by a recent systematic review, which assessed 48 articles showing that IL-6 levels in the blood and CSF of MS patients were not elevated as compared to healthy individuals
[7]. It is also suggested that MS patients with high IL-6 levels be included before designing a new study to examine the effect of exercise. Moreover, because exercise causes the release of IL-6 in skeletal muscles, peritendinous tissues, and the brain
[26], it may be useful for future studies to also examine IL-6 levels in the blood, skeletal muscles, and CSF after intervention. In contrast to earlier findings
[30], three studies with moderate intensity and frequency demonstrated a decrease in cytokine levels after exercise
[24][31][41].
TNF-α is another important proinflammatory cytokine, which was studied in 11 trials. Although this study supports evidence from previous observations
[30], the majority of studies found no significant changes in TNF-α following exercise training
[16][22][23][26][32][33][34], while four trials indicated lower serum levels. According to the review by Bai et al., TNF- α levels in CSF and blood are higher in MS patients. Meanwhile, the reduction in Th1 after exercise is also due to a boost in cortisol and adrenaline levels in response to physical activity, which results in a decline in TNF-α produced by Th1 cells
[29][36]. Only one study observed an increase in TNF-α
[27], which supports the idea of a cytokine boost in serum levels via an increase in their receptors after exercise
[11][30]. The scarcity and weakness of the research, the fluctuation of TNF-α levels after exercise, and the complex role of TNF-α make it difficult to fully interpret the findings. Prior investigations recommended that increased TNF-α in the blood may have a helpful
[37] or harmful
[42] impact on PwMS. For example, while an increase in TNF-α in CSF and blood may be associated with the stage of blood-brain barrier dysfunction
[42], it may also be associated with mild drops in disease relapses
[37]. All of these contradictory findings reveal that the method of training, the timing, and the type of sampling (CSF or blood) may all have an impact on the variations of cytokine production
[11][30].
IFN-γ is released by T cells and natural killer cells, which are not naturally found in the CNS. According to a recent review
[7], IFN-γ levels are moderately increased in MS patients when compared to healthy individuals. Although eight studies in our review showed greater fluctuation after interventions
[23][26][27][34][41][43], our findings support evidence from previous observations showing that IFN-γ is frequently reduced by prolonged and intense activity
[11][44]. This decrease implies that physical activity can naturally decline the number of peripheral blood Th-1 cells and their ability to secrete the proinflammatory cytokine. Despite these discrepancies, our findings indicate that exercise can decline serum interferon levels and the role of IFN-γ after exercise. Nevertheless, additional research into the effects of exercise is required, taking into account the type and intensity, frequency, and duration of exercise, as well as gender.
Another proinflammatory cytokine that plays an important role in immunopathology is IL-17, which is found in the CSF and blood of PwMS patients, with a large increase during relapses
[39]. Contrary to previous expectations
[11], this study showed a decrease in IL-17 serum levels, which had a beneficial impact on the amount of inflammation in PwMS patients who were in the stable/remission phase and were relapse-free for at least 2 months. Moreover, this could be related to the flow of the protocol in the intervention method. The IL-12 family has also been reported to have moderate blood and CSF levels in PwMS. However, there has been less discussion about these two cytokines in the previous literature
[11][30], and our results did not show consistent changes in serum levels. As such, this information was insufficient to provide a definitive assessment of the factors affecting IL-12 family levels.
2.2. Anti-Inflammatory Cytokines
IL-10 is an anti-inflammatory cytokine of the Th2 type that causes disease improvement, remission, and recovery periods in PwMS
[31]. It was the third most evaluated cytokines among studies
[16][22][23][26][31][32][33][34][45][46], with five studies finding no significant changes. Although these findings support the outcomes of previous reviews
[11][30], the majority of trials showed no statistically significant changes. This outcome was reflected by Bai et al. (2019), who evaluated 24 studies and did not reveal a difference in blood serum levels of IL-10 among PwMS and healthy people. Thus, in forthcoming research, more conclusive evidence may be needed to examine IL-10 following the exercise. Furthermore, as IL-6 secretion decreases, IL-10 as an anti-inflammatory marker and TNF-α as a proinflammatory marker increase and decrease, respectively
[22][46], which can manage and improve MS pathogenic functions such as axonal transection and demyelination
[30]. Additionally, the assessment of anti-inflammatory markers such as IL-10 is worthless without considering proinflammatory markers such as IL-6 and TNF-α after exercise. The role of IL-4 in the pathogenesis of MS has been less commonly discussed in the literature. It was evaluated in five studies, and no considerable differences were reported in cytokine levels
[22][26][43]. These results corroborate the findings of many previous studies
[11][30] that showed ambiguous results regarding the effect of exercise on IL-4.
2.3. Adipokines
Adipokines are cytokines that manage and drive the production of proinflammatory cytokines such as TNF-α, as well as boost inflammatory signals and plague development. Leptin was one of the first adipokines to be discovered, and adiponectin is an anti-inflammatory agent
[36]. Our findings reflect the results of Negaresh et al. (2018), who discovered a link between adipokine alternation and fat mass, intensity, and exercise protocol. In general, our study and previous studies
[11][30] did not present adequate results to suggest that exercise programs are useful in modifying adipokine levels in PwMS.
2.4. BDNF
Brain-derived neurotrophic factor is a CNS protein that improves mood or cognition in PwMS
[35], where it was evaluated alongside other inflammatory markers. Szuhany et al. (2015) reported that regular exercise, albeit at a low intensity, can increase the level of BDNF in PwMS. In addition, it was shown that the benefits of these changes may be lower in women than in men. However, our findings do not support previous research
[47]; the limited RCTs evaluated in this study were not adequate to interpret the results.
2.5. Physical and Mental Health as a Secondary Outcome
In 10 studies, mental and physical factors and inflammatory markers were measured simultaneously
[16][20][22][23][24][28][41][43][45][48]. A few trials indicated a rise and decline in the concurrent accumulation of anti- and proinflammatory markers and an individual’s physical and mental functions. This finding broadly supports a systematic review
[11] which indicated that an increase or decrease in anti- and proinflammatory markers was not necessarily correlated with an improvement in mental and physical factors after exercise. On the other hand, these findings may be because of the limited experimental trials performed to ascertain this correlation between inflammatory markers and mental and physical health among PwMS. There is abundant room for further progress in determining the correlation of physical and mental factors with a wider range of inflammatory markers after exercise. Furthermore, using different methodologies, such as large sample size and long duration, may yield different results for future research. As such, exercise may be introduced as a complementary therapy that can improve physical and mental function in PwMS.
This entry is adapted from the peer-reviewed paper 10.3390/ijerph19138151