The role of NF-κB transcription factor in the regulation of cytokine induced thermal hyperalgesia in a Leishmania major model in BALB/c mice

Abstract

Cutaneous leishmaniasis caused mainly by Leishmania major (L. major) is one of the trending models used to investigate induced hyperalgesia and the involved cytokines. Previous studies approached the role of several cytokines in the observed hyperalgesia, but the molecular mechanisms orchestrating such a response still needed to be addressed. In this study, we inspect the role of the NF-κB in the modulation of L. major-prompted hyperalgesia and cytokine expression in BALB/c mice by administering celastrol, a potent blocker of this transcription factor. Intraperitoneal injection of 0.5 mg/kg and 1 mg/kg of celastrol attenuated the L. major-induced thermal hyperalgesia in BALB/c mice for 15 days and 21 days, respectively, as detected by hot plate and tail flick behavioral assessments. Cytokine levels were quantified in the infected paws of BALB/c mice using Sandwich ELISA. The administration of 1 mg/kg celastrol decreased TNF-α levels in L. major infected mice for 23 days, and IL-1β expression declined significantly for 23 days using both celastrol dosages. However, no significant change was observed in the levels of IL-10 in our experimental groups. The activation of NF-κB was detected by observing the phosphorylation levels of the p65 subunit using PathScan phospho-ELISA. The level of NF-κB phosphorylation was elevated in L. major infected BALB/c mice. Only administering 1 mg/kg celastrol suppressed the phosphorylation of p65, thus inactivating NF-kB. In conclusion, our results provide new insights into the correlation between the activation of NF-kB, the induction of thermal hyperalgesia, and the expression of TNF-α and IL-1β in the L. major-induced hyperalgesia model.