Oxidative stress leads to elevated cytokines, excessive structural damage and angiogenesis

Stress destroys structure

Key Points

Highlight:

• Measuring the "IL-10" level may help in better management of endometriosis.

Importance:

• As a result of oxidative stress, elevated cytokine levels in endometriosis activate the process of excessive extracellular matrix degradation, and angiogenesis.

What has been done:

This study investigated the interplay between molecules involved in inflammation, angiogenesis, and extracellular matrix degradation in women with endometriosis.

• Serum samples were collected from 80 women with endometriosis and 80 control women with tubal factor infertility.
• The levels of cytokines (interleukin (IL)-1β, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta, IL-4, -10, -2, -6, -8), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, -9, tissue inhibitor of metalloproteinases (TIMP)-1, -2, and cyclooxygenase (COX)-2 were measured using ELISA assays.
• The level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in peripheral blood mononuclear cells was also measured using flow cytometry.

Results:

• The levels of cytokines, VEGF, MMPs, and COX-2 were higher in the endometriosis group than the control group, while TIMP was lower.  
• The cytokine, IL-10, was able to discriminate endometriosis from control samples.

Limitation:

• The types and stages of endometriosis examined were not disclosed.  
• The importance of the serum data presented needs to be further confirmed with larger sample size.

Lay Summary

Endometriosis is characterized by elevated intracellular reactive oxygen species, which is then believed to upregulate inflammatory cytokines. Reactive oxygen species also regulate the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which is closely linked with immune responses.  Cytokines, which are secreted by immune cells, are produced by endometriotic implants, where they appear to have crucial roles in the development and progression of endometriosis.  Cytokines may induce degradation of the extracellular matrix, which is carried out by matrix metalloproteinases (MMPs) enzymes. More recently, reactive oxygen species are believed to regulate mediators of inflammation, angiogenesis, and matrix degradation. These processes may be interrelated. However, their exact interplay in the context of endometriosis development and progression is not well understood despite numerous evidence that these factors play key roles in the pathogenesis of endometriosis.

Nanda et al at the Department of Biotechnology, National Institute of Technology, Arunachal Pradesh, India, investigated inflammatory, angiogenic, and extracellular matrix degradation molecules in patients with endometriosis, in order to study their role in disease pathogenesis. The study was published in the Annals of Laboratory Medicine.

Blood samples from 80 women with endometriosis were collected at Pratiksha Hospital, Guwahati, Assam, India. Endometriosis in these women was confirmed by diagnostic laparoscopy followed by a biopsy. At the same time, 80 blood samples were also collected from women with tubal factor infertility as controls. Serum was isolated from these blood, after which the levels of interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-β1), IL-4, -10, -2, -6, -8, VEGF, MMP-2, -9, tissue inhibitor of metalloproteinase (TIMP)-1, -2, and cyclooxygenase-2 (COX-2) were measured using ELISA assay. The expression of NF-κB was also determined in the peripheral blood mononuclear cells.

The results show that as compared to the controls, serum from women with endometriosis showed (i) higher estrogen; (ii) higher levels of all cytokine tested; (iii) higher VEGF; (iv) higher MMP-2, -9; and (v) higher COX-2. On the other hand, TIMP-1 and -2 levels were lower in women with endometriosis than in controls. NF-κB expression was increased in endometriosis than controls. Further multivariate statistical analysis identified that IL-10 was the most significant variable that can discriminate endometriosis samples from controls.

According to these results, the authors hypothesized that excessive oxidative stress in endometriosis induces NF-κB, which then stimulates increased cytokine production. The elevated cytokine levels, including IL-10, activate MMPs, which then lead to excessive extracellular matrix degradation and angiogenesis observed as part of the pathogenesis of endometriosis.  

Deregulation of NF-κB activation by OS activates and deregulates the expression of various cytokines which further up-regulate IL-10, which results in excessive ECM degradation and angiogenesis. Moreover, IL-10 emerged as the most important molecule involved in the pathogenesis of endometriosis. Measurement of these molecules may help in better management of the patients with endometriosis.

Research Source: https://pubmed.ncbi.nlm.nih.gov/32311852/?from_term=endometriosis&from_sort=date&from_size=100&from_pos=28