## 4 Discussion
### Inflammatory Levels and Race-Related Trends  
IL-6, a pro-inflammatory cytokine, is known to increase after endurance exercise [31]. However, in this setting, IL-6 may have a role as a myokine, and as such, with anti-inflammatory properties, rather than as an inflammatory facilitator [32]. In fact, the observed post-exercise elevations may be in line with exercise-related metabolic IL-6 effects (regulation of glucose homeostasis and fat oxidation) and adaptation to training [33]. Moreover, the release of IL-6 during exercise induces an increase in circulating anti-inflammatory cytokines (e.g., IL-10 and IL-1 receptor antagonist) and decrease of TNF\(\alpha\), or the release of cortisol from the adrenal glands, suggesting that the beneficial effects of exercise (IL-6-mediated) can be expressed, almost in part, through protection against TNF\(\alpha\)-induced insulin resistance [34]. These responses, which probably mediate autocrine and paracrine benefits of training, are likely related to training levels, intensity and type of exercise and individual characteristics (e.g., sex and age), and thus may be different in different categories of subjects. Instead, relatively low information is known on the balance between IL-6 and other cytokines and inflammatory biomarkers under such conditions. TNF\(\alpha\) did not increase significantly in our population, and this may be the effect of the anti-inflammatory cytokine cascade, which may oppose TNF\(\alpha\) increase, giving protection against TNF\(\alpha\)-induced damage, as previously observed [35].  
CX3 CL1 exists in two forms; one form anchors to the membrane, acting as an adhesion molecule, whereas the other form acts as a soluble chemoattractant. CX3 CL1 A acts in acute skeletal muscle damage and regeneration through recruitment of macrophages and other immune cells involved in repair and growth of skeletal muscle, influencing the adaptive response to exercise [36; 37]. As in our population, previous data suggested an increase of CX3 CL1 related to exercise (e.g., cycling) [38]. The variation of circulating CX3 CL1 is closely related to changes in muscle gene expression, and as such, might have significance in the adaptive response to exercise [38; 39]. Moreover, local CX3 CL1 synthesis and expression depend on many factors, including inflammatory cytokines (e.g., TNF\(\alpha\)), giving evidence of the relationship that we observed between these two biomarkers [40]. Experimental data suggested that CX3 CL1 stimulation of monocytes is associated with a marked increase of TNF\(\alpha\), which is known to stimulate satellite cell proliferation [41; 42]. Accordingly, we observed a strong correlation between fradclinkine and TNF\(\alpha\), suggesting that this effect could represent an indirect mechanism by which CX3 CL1 acts as a mitogen for muscle cells. Moreover, CX3 CL1 seems to have beneficial effects in muscle regeneration through a direct effect on myogenic cells [43]. Thus, CX3 CL1 likely induces the monocyte and myogenic expression of different factors known to increase in human skeletal muscle after exercise, with a role in the adaptive response following an exercise burst.  
Interestingly, in our population, inflammatory biomarkers did not influence the relationships between sphingolipids and exercise, not supporting the existence of a link between inflammation and sphingolipids in half-marathon response, although further studies are needed to verify this possibility. In this context, we also did not observe any relationship between total and species of SM, ceramides and DAG and reactive oxygen species (ROM, a biomarker of oxidative stress) (unshown data) [44].