A cell-penetrating peptide blocks Toll-like receptor-mediated downstream signaling and ameliorates autoimmune and inflammatory diseases in mice

Kwon, Hyuk‐Kwon; Patra, Mahesh Chandra; Shin, Hyeon-Jun; Gui, Xiangai; Achek, Asma; Suresh, Paladugu; Kim, Dong-Jin; Song, S.-Y.; Hong, Riwon; Kim, Kyoung Soo; Kim, Yang‐Gyun; Lee, Francis Y.; Hahm, Dae‐Hyun; Lee, Sang Ho; Choi, Sangdun

doi:10.1038/s12276-019-0244-0

Cited by 21 publications

(20 citation statements)

References 56 publications

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“…Carrageenan-induced peritonitis is a model with initial local inflammation in the peritoneal cavity followed by the development of a general inflammatory response [ 76 , 77 ]. However, despite the differences in the initiation of these inflammatory models, both LPS-induced endotoxemia and carrageenan-induced peritonitis proceed via TLR4 activation [ 78 , 79 ].…”

Section: Resultsmentioning

confidence: 99%

Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

Markov

Sen’kova

Babich

et al. 2020

IJMS

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Plant-extracted triterpenoids belong to a class of bioactive compounds with pleotropic functions, including antioxidant, anti-cancer, and anti-inflammatory effects. In this work, we investigated the anti-inflammatory and anti-oxidative activities of a semisynthetic derivative of 18βH-glycyrrhetinic acid (18βH-GA), soloxolone methyl (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate, or SM) in vitro on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and in vivo in models of acute inflammation: LPS-induced endotoxemia and carrageenan-induced peritonitis. SM used at non-cytotoxic concentrations was found to attenuate the production of reactive oxygen species and nitric oxide (II) and increase the level of reduced glutathione production by LPS-stimulated RAW264.7 cells. Moreover, SM strongly suppressed the phagocytic and migration activity of activated macrophages. These effects were found to be associated with the stimulation of heme oxigenase-1 (HO-1) expression, as well as with the inhibition of nuclear factor-κB (NF-κB) and Akt phosphorylation. Surprisingly, it was found that SM significantly enhanced LPS-induced expression of the pro-inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in RAW264.7 cells via activation of the c-Jun/Toll-like receptor 4 (TLR4) signaling axis. In vivo pre-exposure treatment with SM effectively inhibited the development of carrageenan-induced acute inflammation in the peritoneal cavity, but it did not improve LPS-induced inflammation in the endotoxemia model.

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Section: Resultsmentioning

confidence: 99%

Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

Markov

Sen’kova

Babich

et al. 2020

IJMS

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“…On the other hand, hPP3 (KPKRKRRKKKGHGWSR) derived from human nuclear body protein could enter cells in vitro, at a concentration-, incubation time-, serum-and temperature-dependent manner [172]. It was interesting that a CPP (TIP1) derived from toll/interleukin-1 receptor (TIR) domain-containing adapter protein suppressed toll-like receptor-mediated downstream signaling and showed therapeutic potential for TLR-mediated autoimmune and inflammatory diseases [173]. Gros et al improved a novel method for delivery of proteins, peptides, and antibodies in vitro and in vivo, with no chemical conjugation between the cargo and CPP [101].…”

Section: Peptide and Protein Deliverymentioning

confidence: 99%

Cell penetrating peptides: the potent multi-cargo intracellular carriers

Kardani

Milani

Shabani

et al. 2019

Expert Opinion on Drug Delivery

133

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Introduction: Cell penetrating peptides (CPPs) known as protein translocation domains (PTD), membrane translocating sequences (MTS), or Trojan peptides (TP) are able to cross biological membranes without clear toxicity using different mechanisms, and facilitate the intracellular delivery of a variety of bioactive cargos. CPPs could overcome some limitations of drug delivery and combat resistant strains against a broad range of diseases. Despite delivery of different therapeutic molecules by CPPs, they lack cell specificity and have a short duration of action. These limitations led to design of combined cargo delivery systems and subsequently improvement of their clinical applications. Areas covered: This review covers all our studies and other researchers in different aspects of CPPs such as classification, uptake mechanisms, and biomedical applications. Expert opinion: Due to low cytotoxicity of CPPs as compared to other carriers and final degradation to amino acids, they are suitable for preclinical and clinical studies. Generally, the efficiency of CPPs was suitable to penetrate the cell membrane and deliver different cargos to specific intracellular sites. However, no CPP-based therapeutic approach has approved by FDA, yet; because there are some disadvantages for CPPs including short half-life in blood, and nonspecific CPP-mediated delivery to normal tissue. Thus, some methods were used to develop the functions of CPPs in vitro and in vivo including the augmentation of cell specificity by activatable CPPs, specific transport into cell organelles by insertion of corresponding localization sequences, incorporation of CPPs into multifunctional dendrimeric or liposomal nanocarriers to improve selectivity and efficiency especially in tumor cells.

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“…Lastly, we did not investigate whether TIP1 itself is harmful to the kidneys. Nonetheless, the amount of TIP1 administered was within the range in which cytotoxic effects were not observed in either HEK-Blue hTLR4 or RAW 264.7 cell lines [16].…”

Section: Discussionmentioning

confidence: 93%

“…For the effective delivery of TIP1 to the required site of action, we conjugated TIP1 to a cell-penetrating peptide (CPP), making a peptide of 24 amino acids with a formula weight of 3168 g/mol ( Figure 1). Previously, we demonstrated that CPP-linked TIP1 (hereafter referred to as TIP1) blocked signal transduction of multiple TLRs, with the strongest effect on TLR4 [16]. In addition, this biological action was shown to lead to attenuated tissue damage in animal models of sepsis and inflammatory arthritis.…”

Section: Introductionmentioning

confidence: 99%

A Cell-Penetrating Peptide That Blocks Toll-Like Receptor Signaling Protects Kidneys against Ischemia-Reperfusion Injury

Jung

Seo

Park

et al. 2021

IJMS

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Renal ischemia-reperfusion injury (IRI) is involved in the majority of clinical conditions that manifest as renal function deterioration; however, specific treatment for this type of injury is still far from clinical use. Since Toll-like receptor (TLR)-mediated signaling is a key mediator of IRI, we examined the effect of a multiple-TLR-blocking peptide named TLR-inhibitory peptide 1 (TIP1), which exerts the strongest action on TLR4, on renal IRI. We subjected C57BL/6 mice to 23 min of renal pedicle clamping preceded by intraperitoneal injection with a vehicle or TIP1. Sham control mice underwent flank incision only. Mouse kidneys were harvested after 24 h of reperfusion for histology, western blot, RT-PCR, and flow cytometry analysis. Pretreatment with TIP1 lowered the magnitude of elevated plasma creatinine levels and attenuated tubular injury. TIP1 treatment also reduced mRNA expression of inflammatory cytokines and decreased apoptotic cells and oxidative stress in post-ischemic kidneys. In kidneys pretreated with TIP1, the infiltration of macrophages and T helper 17 cells was less abundant than those in the IRI only group. These results suggest that TIP1 has a potential beneficial effect in attenuating the degree of kidney damage induced by IRI.

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A cell-penetrating peptide blocks Toll-like receptor-mediated downstream signaling and ameliorates autoimmune and inflammatory diseases in mice

Cited by 21 publications

References 56 publications

Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

Cell penetrating peptides: the potent multi-cargo intracellular carriers

A Cell-Penetrating Peptide That Blocks Toll-Like Receptor Signaling Protects Kidneys against Ischemia-Reperfusion Injury

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