Soluble mediators in plasma from irritable bowel syndrome patients excite rat submucosal neurons

Neuroimmune Cross Talk in the Gut. Neuroendocrine and neuroimmune pathways contribute to the pathophysiology of irritable bowel syndrome

“…Cytokines facilitate cell-to-cell signaling in an immune response, but may also participate in modulating intrinsic and afferent nerve activity. Indeed, IL-6 (6, 63), IL-1β (86) and tumor necrosis factor α (72) have direct actions on enteric neuronal activation and we observed that the neurostimulatory effects of IBS plasma on rat submucosal and myenteric neurons is dependent on IL-6, IL-8 and CRF (6,62). Such cytokines stimulate sensitization of nociceptors, which would increase the excitability of afferent endings innervating the colon.…”

Activation of colo‐rectal high‐threshold afferent nerves by Interleukin‐2 is tetrodotoxin‐sensitive and upregulated in a mouse model of chronic visceral hypersensitivity

“…Application of supernatants from patient tissue or immune mediators to animal nerve preparations has been fundamental to understanding how altered immune function impacts on viscero‐sensory and enteric nerve function in disease states such as IBS . Cultured mucosal biopsy and PBMC supernatants from IBS patients typically excite in vitro animal preparations of intestinal enteric and extrinsic afferent nerves while those from healthy subjects either have no effect or inhibit nerve activity . Our finding that IL‐2 causes potent direct firing of colo‐rectal afferent endings is the first description of its effect on GI afferent endings.…”

“…Extrinsic colo‐rectal afferents signal sensory information, including pain, from the large intestine to the central nervous system via the spinal cord . The majority of studies investigating the effects of immune mediators on GI nerves have focused on mediators primarily secreted by innate immune cells, including mast cells and monocyte/macrophages, in healthy animals . In contrast, the cytokine IL‐2 is principally secreted by T cells, which are a major component of the adaptive arm of the immune response.…”

“…Our finding that IL‐2 causes potent direct firing of colo‐rectal afferent endings is the first description of its effect on GI afferent endings. Further, it is also the first description that a cytokine primarily attributed to adaptive immune cells can modulate colo‐rectal afferent nerve activity, as the immune mediators outlined above are either primarily secreted by innate immune cells (e.g., proteases, histamine, and IL‐1 β ), by either innate or adaptive immune cells (e.g., IL‐6 and TNF‐ α ) or do not affect colo‐rectal afferent function (e.g., IL‐10) …”

“…Much of this evidence currently pertains to innate immune cells, including mast cells and monocyte/macrophages, which have been shown to be altered in number and function in IBS patients relative to healthy subjects . Mast cell mediators and cytokines including TNF‐ α , interleukin‐6 (IL‐6) and IL‐1 β modulate colo‐rectal afferent excitability, but these cytokines may all be attributed to innate immune responses . However, T cell number and activation state is also altered in IBS indicating alterations are also apparent in the adaptive arm of the immune response .…”