Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation
Fig 6
Newly identified NBD mimetics suppress LPS-induced acute inflammation in vivo.
(A) The bioavailability property of SR12460, SR12343, SR12454, and SR11481. Concentrations of NBD mimetics were determined in plasma, brain, muscle, spleen, and liver 2 h post a single i.p. injection of 10 mg/kg of drugs; n = 3 per group. (B) Shown is the model to induce LPS-mediated acute inflammation and the treatment regimen with NBD mimetics. Mouse image via http://www.clker.com/clipart-mice-blank.html (copyright-free). (C) NBD mimetics suppressed LPS-induced acute inflammation in liver and lung by down-regulating NF-κB target gene expression. Vehicle, SR12343, SR12460, and 8K-NBD peptide were dosed at 10 mg/kg 30 min prior to the LPS treatment. Acute inflammation was induced by i.p. injection of 10 mg/kg LPS. Lung and liver were collected 2–4 h post injection, and mRNA was extracted for qRT-PCR analysis. (D, E) Western blot analysis was performed to probe for the expression of p-IκBα and COX-2 at protein level in liver and lung tissues. (F) Serum levels of IL-6 were determine by ELISA. n = 3–8 each group. *P < 0.05, **P < 0.01. Underlying data can be found in S1 Data. COX-2, cyclooxygenase 2; IL-6, interleukin 6; i.p., intraperitoneal; LPS, lipopolysaccharide; NBD, NEMO-binding domain; n.d., nondetectable; NEMO, NF-κB essential modulator; NF-κB, nuclear factor κB; qRT-PCR, quantitative real-time polymerase chain reaction.