The Pro-Inflammatory Cytokines IL-1 and TNF Are Neurotrophic for Enteric Neurons

Intestinal inflammation causes initial axonal degeneration and neuronal death but subsequent axon outgrowth from surviving neurons restores innervation density to the target smooth muscle cells. Elsewhere, the pro-inflammatory cytokines TNFα and IL-1β cause neurotoxicity, leading us to test their role in promoting enteric neuron death. In a rat coculture model, TNFα or IL-1β did not affect neuron number but did promote significant neurite outgrowth to twofold that of control by 48 h, while other cytokines (e.g., IL-4, TGFβ) were without effect. TNFα or IL-1β activated the NFκB signaling pathway, and inhibition of NFκB signaling blocked the stimulation of neurite growth. However, nuclear translocation of NFκB in smooth muscle cells but not in adjacent neurons suggested a dominant role for smooth muscle cells. TNFα or IL-1β sharply increased both mRNA and protein for GDNF, while the neurotrophic effects of TNFα or IL-1β were blocked by the RET-receptor blocker vandetanib. Conditioned medium from cytokine-treated smooth muscle cells mimicked the neurotrophic effect, inferring that TNFα and IL-1β promote neurite growth through NFκB-dependent induction of glial cell line-derived neurotrophic factor (GDNF) expression in intestinal smooth muscle cells. In vivo, TNBS-colitis caused early nuclear translocation of NFκB in smooth muscle cells. Conditioned medium from the intact smooth muscle of the inflamed colon caused a 2.5-fold increase in neurite number in cocultures, while Western blotting showed a substantial increase in GDNF protein. Pro-inflammatory cytokines promote neurite growth through upregulation of GDNF, a novel process that may facilitate re-innervation of smooth muscle cells and a return to homeostasis following initial damage.