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bioRxiv · 10.64898/2026.05.15.725418

Inhibition of TYK2 attenuates hyper IL-6- and Oncostatin M-mediated Calcium Signalling in Sensory Neurons

Pritchard, T. A.·Gupta, R.·Higham, J.·Aziz, Q.·Bulmer, D.
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Abstract

Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an in silico analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.

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Pritchard, T. A., Gupta, R., Higham, J., Aziz, Q., Bulmer, D.. 2026-05-19. Inhibition of TYK2 attenuates hyper IL-6- and Oncostatin M-mediated Calcium Signalling in Sensory Neurons. https://doi.org/10.64898/2026.05.15.725418

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