Do IL-6 and IL-17 drive chronic musculoskeletal pain and fatigue?

The relationship between pro-inflammatory cytokines and the pathophysiology of chronic pain and fatigue is well-established, with interleukins 6 (IL-6) and 17 (IL-17) acting as primary drivers of these conditions. These molecules operate across both the peripheral and central nervous systems to amplify sensory signals and alter systemic energy levels.

Clinical and effectiveness evidence

In clinical populations, such as those with rheumatoid arthritis and spondyloarthritis, the role of these cytokines is highlighted by the effectiveness of targeted therapies. Randomized controlled trials have demonstrated that blocking IL-6 (e.g., with tocilizumab) or IL-17 (e.g., with secukinumab) significantly reduces patient-reported fatigue scores and joint pain. Furthermore, Mendelian randomization studies provide evidence for a causal link between elevated IL-6 signaling and the risk of developing chronic pain across multiple anatomical sites.

Mechanistic explanations

The amplification of pain and fatigue occurs through several distinct biological pathways:

• Peripheral Sensitization: IL-6 activates the JAK/STAT3 and PI3K pathways, which sensitize TRPV1 ion channels on nociceptors, lowering the threshold for pain signals. Simultaneously, IL-17 receptors on C- and Aδ-fibers directly enhance neuronal excitability in peripheral tissues.
• Central Sensitization: IL-6 promotes spinal plasticity and microglial activation. This triggers the release of brain-derived neurotrophic factor (BDNF), which strengthens excitatory synaptic transmission while weakening inhibitory controls in the spinal dorsal horn.
• Blood-Brain Barrier (BBB) Disruption: IL-6 and IL-17 can synergistically reduce tight junction proteins (like ZO-1 and claudin-5), increasing BBB permeability. This allows peripheral inflammatory mediators to enter the central nervous system, fostering neuroinflammation.
• Sickness Behavior: These cytokines induce a state known as "sickness behavior," characterized by lethargy and reduced activity, which serves as the biological basis for the profound fatigue observed in chronic inflammatory states.

Bottom line

Pro-inflammatory cytokines IL-6 and IL-17 are fundamental mediators of chronic musculoskeletal pain and fatigue. They drive these symptoms by sensitizing peripheral nerves, inducing central neuroinflammation, and disrupting the blood-brain barrier.