Statins prevent chronic inflammation-related cancers by inhibiting interleukin-33

In a recently published study, Nature CommunicationsThe researchers investigated the effects of statins through inhibition of interleukin-33 (IL-33).

This epithelium-derived alarmin cytokine promotes chronic inflammation by activating type 2 immune responses associated with chronic inflammatory diseases.

study: Statins prevent cancer development in chronic inflammation by inhibiting interleukin-33 expressionImage credit: roger ashford/Shutterstock.com

background

Chronic inflammation is a major cause of cancer worldwide, driving the prevalence of diseases such as inflammatory bowel disease (IBD), pancreatitis, hepatitis, etc. Immune factors and cells such as mast cells, M2 macrophages, interleukin-10, interleukin-13, and transforming growth factor beta (TGF-β) contribute to carcinogenesis.

Given that effector molecules are involved in promoting cancer, it is challenging to prevent cancer by inhibiting effector molecules.

Anti-inflammatory drugs such as dexamethasone have significant side effects, so it is important to discover safe molecules to reduce chronic inflammatory responses and avoid cancer complications.

IL-33 is a major inducer of chronic inflammation that leads to cancer, but the mechanisms underlying this are still unclear.

About the Research

In this study, the researchers investigated the potential of IL-33 and its receptor ST2 as targets to disrupt the chronic inflammatory environment associated with diseases such as inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), hepatitis, and pancreatitis.

The researchers investigated the effect of interleukin-33 on chronic inflammation in mice. They subjected wild-type mice to models of chronic inflammation, including dermatitis and pancreatitis.

The researchers administered 2,4-dinitro-1-fluorobenzene topically to mice to induce dermatitis, and injected the animals intraperitoneally with caerulein in phosphate-buffered saline (PBS) to induce pancreatitis, with both treatments lasting for 22 days.

The research team performed ribonucleic acid (RNA) sequencing analysis of PBS in epidermal keratinocytes from mice treated with 2,4-dinitro-1-fluorobenzene (DNFB) and mice treated with acetone and caerulein (control), and elucidated the signaling mechanism that causes IL-33-associated chronic inflammation.

The researchers investigated Toll-like receptor 3/4 (TLR3/4) signaling activation, the Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-β (TRIF), and the myeloid differentiation primary response 88 (MyD88) adaptor protein.

The researchers further investigated whether interleukin-33 expression occurs downstream of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) signaling by treating epithelial cells with polyinosinic-polycytidylic acid (poly(I:C)) and lipopolysaccharide (LPS).

The researchers also subjected Irf3 knockout mice to a chronic inflammatory state. To find small molecule IL-33 inhibitors, the researchers searched a U.S. Food and Drug Administration (FDA)-approved drug library using a luciferase-based Il33 expression test. The researchers confirmed their findings by testing the effects of pitavastatin on the TBK1-IRF3 pathway in pancreatic cell lines.

The team found that geranylgeranyl diphosphate (GGPP)-mediated prenylation may target the regulation of TBK1, as the prenylation inhibitor GGTI-2147 blocked the membrane localization and phosphorylation of TBK1.

The researchers also evaluated pitavastatin's ability to reduce IL-33 and suppress inflammatory processes in the body. They administered DNFB topically to the back skin of mice for 22 days and pitavastatin for three weeks to examine the effects on chronic pancreatitis.

To examine the effects of caerulein injections in mice, the researchers used a model of chronic pancreatitis-associated pancreatic cancer. They examined the expression of IL-33 and IRF3 in epithelial cells from 15 identical samples of normal pancreas, pancreatitis, and pancreatic ductal adenocarcinoma.

The researchers also used epidemiological methods to study the effect of pitavastatin on chronic pancreatitis and pancreatic cancer risk in humans. They compared patient cohorts from the TriNetX Diamond Network, which contains more than 200 million electronic medical records.

result

This study found that environmental stimuli activated the Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway, leading to IL-33 induction in the skin and pancreas.

Pitavastatin significantly reduces interleukin-33 levels by inhibiting TBK1 membrane recruitment and activation via the mevalonate pathway Pitavastatin prevents chronic pancreatitis and associated complications in an IL-33-dependent manner.

TLR3/4 signaling is a key regulator of interleukin-33 levels during chronic inflammation Statins inhibited interleukin-33 expression by modulating TBK1 signaling in cancer-prone chronic inflammation.

Pitavastatin reduced membrane-bound and phosphorylated TBK1 (p-TBK1) by inhibiting the mevalonate pathway, reducing the risk of pancreatitis and pancreatic ductal adenocarcinoma (PDAC) in rats and humans.

TriF-mediated TBK1-IRF3 signaling affects IL-33 levels, with higher phosphorylation in DNFB-treated skin and caerulein-treated pancreas compared with controls.

TBK1-IRF3 signaling promotes IRF3 target genes, tumor necrosis factor (TNF), chemokine interferon-gamma-inducible protein 10 (CCXL10), and IL-1β.Irf3KO skin and pancreas treatment with DNFB and cerulein reduced IL-33 levels, mast cell population, and epidermal thickness.

Five FDA-approved small molecule compounds reduced IL-33/control luminescence absorbance to less than 40%. Pitavastatin and zoledronic acid also suppressed poly(I:C)-induced IL-33 levels.

Conclusion

This study found that statins can reduce cancer-driving chronic inflammation by inhibiting the TBK1-IRF3-IL-33 signaling pathway. Lipophilic statins are a safe and effective preventive option. The mevalonate pathway controls TBK1-IRF3 signaling, which may be essential for phosphorylation and activation.

Findings further demonstrate that GGPP increases membrane localization of key signaling molecules.

Statins are a group of safe chemopreventive drugs that reduce chronic inflammation and its associated cancer-related consequences, and may represent a new therapeutic approach for skin-related chronic inflammation.