Antinociceptive interactions between excitatory interferon-γ and interleukin-17 in sensory neurons

Interferon-γ (IFNγ) and interleukin-17 (IL-17) are master regulators of innate and adaptive immunity. Here we asked whether these cytokines also regulate pain. Both cytokines increased the excitability of isolated small- to medium-sized sensory neurons, suggesting a pronociceptive effect. However, in vivo IL-17 was pronociceptive, whereas IFNγ was antinociceptive. Co-administration of IFNγ and IL-17 in vivo resulted in antinociception. Pre-incubation with IFNγ also eliminated the increase in excitability by interleukin-17A in isolated sensory neurons, demonstrating that the excitatory membrane effects of IFNγ can interfere with the excitatory membrane effects of IL-17, resulting in neuronal inhibition. IFNγ increased TTX-sensitive Na⁺ currents, while IL-17 increased TTX-resistant Na⁺ currents. Blocking TTX-sensitive Na⁺ currents eliminated the inhibition of the IL-17 effect by IFNγ. We propose a novel form of inhibition in sensory neurons that allows the intrinsically excitatory IFNγ to attenuate pro-nociceptive effects of cytokines such as IL-17 through interactions with voltage-gated Na⁺ currents.