Atherosclerosis is characterized, as an inflammatory disorder in the circulatory system, with increasing tendency toward mortality and morbidity. Thus, developing novel therapeutic targeting inflammation is necessary. Here, we investigated the effects of interleukin‐36 receptor antagonist (IL‐36RN), a newly identified anti‐inflammatory factor, on atherosclerosis. The regulation of NLRP3 inflammasome by IL‐36RN was determined in vitro in macrophage cells after oxidized low‐density lipoprotein (ox‐LDL) stimulation. The IL‐1β and caspase‐1 p10 secretion were assessed by enzyme‐linked immunosorbent assay and western blot analysis. Finally, the IL‐36RN/NLRP3 inflammasome pathway was confirmed in apolipoprotein E‐deficient mice. IL‐36RN suppressed the expression of NLRP3, the secretion of IL‐1β, and caspase‐1 p10 in vitro, while IL‐36 pathway stimulation activated the NLRP3 inflammasome, which was inhibited by IL‐36RN. In the mouse model of atherosclerosis, IL‐36RN delivered by the lentivirus vector inhibited the development of atherosclerosis, and the atheroprotective effects of IL‐36RN were attenuated by IL‐36 pathway stimulation. Furthermore, the regulation of NLRP3 inflammasome by IL‐36RN was also confirmed in vivo. We demonstrated here that IL‐36RN exerted atheroprotective functions through IL‐36RN/NLRP3 inflammasome pathway.
In this study, we evaluated the effects of Cyclosporine A (CsA) on Lipopolysaccharide (LPS)-induced cytokine production in the genital tract of female rabbits. Twelve sexually mature and healthy female rabbits were randomly divided into four groups (n = 3 each). The rabbits in the LPS group were given an intrauterine infusion of Escherichia coli LPS (4 mg/kg body weight (BW)). Rabbits in the CsA group were given CsA (20 mg/kg BW). Rabbits in the LPS + CsA group were given LPS (4 mg/kg BW) and CsA (20 mg/kg BW). The control group received only LPS and CsA carrier. The gene expression and protein levels of pro- and anti-inflammatory cytokines were observed using qRT-PCR and immuno-histochemical (IHC) assay, respectively. Our study showed that IL-1β, IL-6, IL-8, TNF-α, IFN-γ, IL-4, IL-10, IL-13, and TGF-β were expressed in female genital organs. The LPS challenge increased the mRNA expression of IL-6 and TNF-α in the uterine body and IL-1β in the uterotubal junction compared to the control group. CsA increased the basal mRNA expression of anti-inflammatory cytokines (i.e., IL-4 in the uterine body, uterotubal junction, and oviductal ampulla; IL-10 in the cervix, oviductal isthmus, and ampulla; and TGF-β in the uterotubal junction and oviductal ampulla) and pro-inflammatory cytokines (i.e., IL-6 and IL-8 in the cervix; IL-1β in the oviductal isthmus; TNF-α in the oviductal ampulla; and IFN-γ in the uterine body compared to the control group). In addition, CsA inhibited the mRNA expression of pro-inflammatory cytokines, such as IL-6 in the uterine body, uterotubal junction, and oviductal isthmus; TNF-α in the uterine body; and IFN-γ in the uterotubal junction and oviductal isthmus induced by the LPS challenge. The IHC assay showed the LPS-induced increase in protein production of IL-6 in the uterine body and oviductal isthmus. CsA increased the protein production of IL-10 in the cervix, uterine body, oviductal ampulla, and isthmus. Moreover, CsA decreased the protein production of IL-6 in the uterine body and oviductal isthmus induced by LPS.
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