Increased expression of the Cbl family of E3 ubiquitin ligases decreases Interleukin-2 production in a rat model of peripheral neuropathy

Ji Seon Jeong,Ha Yeon Kim,Byung Seop Shin,Ae Ryoung Lee,Ja Eun Lee,Ji Hyun Yoon,Tae Soo Hahm

doi:10.1186/s12871-018-0555-z

Abstract

BackgroundInterleukin 2 (IL-2) influences the development and severity of pain due to its antinociceptive and immunomodulatory effects. Its production is influenced by the increased expression of c-Cbl (Casitas B-lineage lymphoma proto-oncogene) and Cbl-b E3 ubiquitin ligases. We evaluated the effects on IL-2-mediated changes in c-Cbl and Cbl-b expression in a rat model of chronic neuropathic pain.MethodsPeripheral neuropathy was induced in adult male Sprague-Dawley rats weighing 250–300 g by chronic spinal nerve ligation. Half of the spinal cord ipsilateral to the nerve injury was harvested at 1, 3, and 6 weeks, and the expression levels of IL-2, c-Cbl, Cbl-b, phospholipase C-γ1 (PLC-γ1), ZAP70, and protein kinase Cθ (PKCθ), as well as ubiquitin conjugation, were evaluated.ResultsTotal IL-2 mRNA levels were significantly decreased at 3 and 6 weeks after nerve injury compared to those in sham-operated rats. The mRNA levels of c-Cbl and Cbl-b, as well as the level of ubiquitin conjugation, were significantly increased at 3 and 6 weeks. In contrast, the levels of phosphorylated ZAP70 and PLC-γ1 were decreased at 3 and 6 weeks after spinal nerve ligation. Ubiquitination of PLC-γ1 and PKCθ was increased at 3 and 6 weeks.ConclusionsOur results suggest that ubiquitin and the E3 ubiquitin ligases c-Cbl and Cbl-b function as neuroimmune modulators in the subacute phase of neuropathic pain after nerve injury.

Highlights

Interleukin 2 (IL-2) influences the development and severity of pain due to its antinociceptive and immunomodulatory effects
We evaluated IL-2 mRNA levels in rats with chronic neuropathic pain induced by spinal nerve ligation, and the effects of changes in c-casitas B lineage lymphoma (Cbl) and Cbl-b expression in T cells on downstream factors in the regulating receptor tyrosine kinase (RTK) signaling pathway including ZAP 70 and phospholipase C-γ1 (PLC-γ1), which influence IL-2 production
C-Cbl, and Cbl-b expression in the spinal cord Because IL-2 mRNA levels significantly decrease after spinal nerve injury, and IL-2 production is significantly decreased by c-Cbl and Cbl-b in the presence of T cell suppression [10], we investigated Cbl-b and c-Cbl levels after nerve injury by western blotting

Summary

Introduction

Interleukin 2 (IL-2) influences the development and severity of pain due to its antinociceptive and immunomodulatory effects. Its production is influenced by the increased expression of c-Cbl (Casitas B-lineage lymphoma proto-oncogene) and Cbl-b E3 ubiquitin ligases. To enable the development of effective treatments, the mechanism(s) underlying neuropathic pain caused by nerve injury have been the focus of numerous studies. In addition to its antinociceptive effects, IL-2 can influence the development, maintenance, and severity of neuropathic pain symptoms by affecting the immune system homeostasis [8]. The casitas B lineage lymphoma (Cbl) proto-oncogene family of E3 ubiquitin ligases are key regulators of T cell function and influence the production of IL-2 by negatively regulating receptor tyrosine kinases (RTKs) signaling in T cells [10, 11]. The mechanism by which IL-2 production is changed in chronic neuropathic pain, where functional changes of T cell occur, is yet to be elucidated

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Conclusion