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

Waśkiewicz Z. Mukhambet Z. Azerbayev D. Bondarev S.
July 2025 Multidisciplinary Digital Publishing Institute (MDPI)

International Journal of Molecular Sciences
2025 #26 Issue 13

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.

C-reactive protein (CPR) , cytokine response , endurance exercise , interleukin-6 (IL-6) , tumor necrosis factor-alpha (TNF-α) , ultramarathon

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Institute of Sport Science, Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, 40-065, Poland
Department of Sport Education and Coaching, Academy of Physical Education and Mass Sport, Astana, 010000, Kazakhstan
Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, Padua, 35122, Italy

Institute of Sport Science
Department of Sport Education and Coaching
Department of Cardiac

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