Parthenolide inhibits LPS-induced inflammatory cytokines through the toll-like receptor 4 signal pathway in THP-1 cells

Abstract

Parthenolide (PTL) shows potent anti-inflammatory and anti-cancer activities. In the present study, the molecular mechanisms of PTL's activities were explored in lipopolysaccharide (LPS)-induced human leukemia monocytic THP-1 cells and human primary monocytes. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay was used to analyze the effect of PTL on THP-1 cell viability. Enzyme-linked immunosorbent assay was used to determine the effect of PTL on LPS-induced inflammatory cytokine secretion. Flow cytometry and quantitative real-time polymerase chain reaction were used to assess the effect of PTL on LPSinduced toll-like receptor 4 (TLR4) expression. Phosphorylation levels of signaling molecules were determined by western blot analysis. Results showed that PTL <12.5 μM did not significantly affect THP-1 cells viability. LPS treatment led to a marked up-regulation of interleukin (IL)-6, IL-1β, IL-8, IL-12p40, tumor necrosis factor-α, IL-18, and NO in THP-1 cells. However, PTL inhibited the expression of these cytokines in a dose-dependent manner, with IC 50 values of 1.091-2.620 μM. PTL blocked TLR4 expression with an IC 50 value of 1.373 μM as determined by the flow cytometry analysis, and this blocking effect was verified at both protein and mRNA levels. Up-regulation of phosphorylation levels of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, p38, nuclear factor κB (NF-κB) p65, and IκBα and up-regulation of expressions of other molecules (inducible nitric oxide synthase, TLR4, and TNF receptor-associated factor 6) induced by LPS were abolished by PTL in a dose-dependent manner. The anti-inflammatory mechanisms of PTL operate partly through the TLR4-mediated mitogen-activated protein kinase and NF-κB signaling pathways. Therefore, TLR4 may be a new target for anti-inflammation therapies.

Activation of STAT3 is a key event in TLR4 signaling-mediated melanoma progression

“…Parthenolide has anti-inflammatory and anticancer activities. It downregulates TLR4 expression in THP-1 monocytes 49 and inhibits activation of NF-κB, a TLR4 downstream transcription factor, in melanoma cells 50 . In addition, parthenolide inhibits STAT3 activation and exerts anticancer effects in breast cancer, gastric cancer, prostate cancer and colon cancer cells 36,51 .…”

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

“…Parthenolide ( Figure 2 ) is a known inhibitor of the TLR4/NF-κB pathway [ 72 ]. It has been observed in human leukemia monocytic THP-1 cells that the LPS-stimulated production of TNF-α, as well as the production of various interleukins (IL-6, IL-1β, IL-8, IL-12p40, IL-18), were reduced more than 50% by the administrating parthenolide.…”

Nonivamide, a capsaicin analogue, exhibits anti‐inflammatory properties in peripheral blood mononuclear cells and U‐937 macrophages

“…Various immune‐active cells serve as model systems to investigate inflammatory processes, commonly using bacterial LPS, naturally found in the outer membrane of Gram‐negative bacteria, to initiate an inflammatory reaction . LPS binds to toll ‐like receptors (TLRs) initiating the onset of different signaling cascades .…”