Inflammatory Response to Ultramarathon Running: A Review of IL-6, CRP, and TNF-α

Ultramarathon running elicits a profound inflammatory response, characterized by significant increases in interleukin-6 (IL-6) and C-reactive protein (CRP), with comparatively modest changes in tumor necrosis factor-alpha (TNF-α). We reviewed approximately 80 field studies of ultramarathon events (distances >42.2 km) that measured IL-6, CRP, and TNF-α before and after races. IL-6 typically spiked immediately post-race-often rising dozens or even thousands of times above baseline-then rapidly declined, usually returning to near baseline within 24-48 h. CRP, an acute-phase protein, exhibited a slower, sustained elevation, peaking 24-72 h after race completion and remaining above baseline for 2-3 days before gradually returning to normal. TNF-α responses were variable: some studies reported small but significant post-race increases (roughly 1.2-1.7-fold above baseline), while others found no significant change in circulating TNF-α despite the extreme effort. Longer race durations and distances generally correlated with higher peak IL-6 and CRP levels. Experienced ultramarathon runners tended to exhibit attenuated inflammatory responses compared with less-trained individuals, and anti-inflammatory cytokines (e.g., IL-10) increased in tandem with IL-6 in well-trained athletes, helping to mitigate TNF-α elevations. In total, 28 studies were included in the final synthesis, and their quality was assessed using the Newcastle-Ottawa Scale. Visual synthesis tools, including a PRISMA flowchart and time course plots, are provided to enhance the narrative's interpretability. In summary, ultramarathon running elicits a robust systemic inflammatory response with distinct temporal patterns for IL-6, CRP, and TNF-α. These findings have important implications for athlete recovery, monitoring, and understanding the physiological limits of the inflammatory response to extreme endurance stress.