Costunolide Improves Psoriasis-like Skin Inflammation Via IL-36 Signal

Objective: Psoriasis is a recurrent inflammatory skin disease.It has been reported that IL-36 cytokines are overexpressed in psoriasis,but the relevant mechanism is not clear.There was no specific drug could treat psoriasis in the current research.Costunolide(Costunolide,Cos)is a sesquiterpene compound and has a variety of pharmacological activities.We established psoriasis-like skin inflammation model in vivo and mice primary dermal fibroblast inflammation model in vitro to explore the related mechanism of costunolide in improving skin inflammation.Methods: 1.A mouse model of psoriasis-like skin inflammation was established by 5%imiquimod(Aldara),BALB/C mice were treated with Cos(20,10 or 5 mg/kg,i.g)or applied DXMS cream 90 mg for 8 days and from the fifth day applied the imiquimod62.5 mg.The mice skin pathomorphological changes were observed by H&E staining,and the protein related to psoriasis,epidermal injury and inflammation were detected by Western Blot,such as IL-36α,IL-36β,IL-36γ,Keratin 1,Keratin 14,Keratin 17,PCNA and P2X7 R,and neutrophil marker MPO and macrophage marker F4/80 were detected by immunofluorescence staining,qPCR experiment was used to detect the mRNA expression levels of Cxcl1,Cxcl2,and Il36 g.2.An inflammation model of mice primary dermal fibroblasts was stimulated by Poly(I:C),the effects of Cos on the survival rate of Raw 264.7,mice primary peritoneal macrophages,NIH3T3 cells and mice primary dermal fibroblasts survival rate were detected by MTT Assay.And Western Blot,ELISA and immunofluorescence staining were used to investigate inflammatory factors,such as IL-36γ,IL-1β and HMGB1.Results: 1.In vivo experimental results showed that Cos improved the symptoms of erythema,silver scales and hyperkeratosis,and inhibit the expressions of PCNA and Keratin 1,Keratin 14,Keratin 17.It could also reduce the expressions of inflammatory factors such as,IL-36α,IL-36β,IL-36γ,P2X7 R,MPO,F4/80,and reduce the mRNA expression levels of Cxcl1,Cxcl2,and Il36 g.2.The results of the vitro model showed that Cos had no toxicity to Raw 264.7,mice primary peritoneal macrophages,NIH3T3 and mice dermal primary fibroblasts,Poly(I:C)could induce the release of inflammatory cytokines such as,IL-36γ after48 h stimulation of mice primary dermal fibroblast,while Cos had an ameliorative effect.Conclusion: The results of experiment showed that Cos improved psoriasis-skin inflammation based on IL-36 signal.In our study,we also found that inflammatory infiltration occurred not only in the epidermis but also in the dermis.And in vitro experiments also proved that Cos could inhibit the release of IL-36 cytokines and other inflammatory cytokines in mice dermal fibroblast induced by Poly(I:C).Our study provides a new candidate drug for the treatment of psoriasis-skin inflammation,and provides a new research idea for the subsequent research of psoriasis-like skin inflammation.