The Pro-Inflammatory Cytokines IL-1β and TNFα 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 TNF alpha and IL-1 beta cause neurotoxicity, leading us to test their role in promoting enteric neuron death. In a rat coculture model, TNF alpha or IL-1 beta 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, TGF beta) were without effect. TNF alpha or IL-1 beta activated the NF kappa B signaling pathway, and inhibition of NF kappa B signaling blocked the stimulation of neurite growth. However, nuclear translocation of NF kappa B in smooth muscle cells but not in adjacent neurons suggested a dominant role for smooth muscle cells. TNF alpha or IL-1 beta sharply increased both mRNA and protein for GDNF, while the neurotrophic effects of TNF alpha or IL-1 beta were blocked by the RET-receptor blocker vandetanib. Conditioned medium from cytokine-treated smooth muscle cells mimicked the neurotrophic effect, inferring that TNF alpha and IL-1 beta promote neurite growth through NF kappa B-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 NF kappa B 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.