Exploring the Influence of IL-8, IL-10, Patient-Reported Pain, and Physical Activity on Endometriosis Severity
Abstract
:1. Introduction
1.1. Endometriosis Development and Biomarkers
- IL-8 (interleukin 8), known as an α-chemokine with chemotactic activity and acting as a strong angiogenic agent, primarily produced by peripheral macrophages, has been detected in high concentrations in peritoneal fluid of women with endometriosis. In addition to its chemotactic and activating properties for granulocytes, IL-8 has recently been found to stimulate the proliferation of endometrial cells [44,45,46,47].
- Vascular endothelial growth factor (VEGF), one of the main angiogenic factors with the ability to stimulate mitogenesis, migration, and differentiation of endothelial cells, is strongly expressed in endometriotic tissue as well as in peritoneal macrophages. Peritoneal-activated macrophages are a major source of VEGF in endometriosis, and this expression is directly regulated by ovarian steroids. E2 acts on various macrophage signaling pathways, especially those related to the support of inflammatory cell recruitment and the remodeling of inflamed tissues, such as mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase/protein kinase B, and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Consequently, dysregulation of ovarian steroid hormone homeostasis could influence the survival of ectopic endometrial cells and promote lesion vascularization. It is well known that hypoxia induces the expression of VEGF. Effects of hypoxia are mainly mediated by a protein complex called hypoxia-inducible factor-1 (HIF-1), which consists of two subunits, HIF-lα, the inducible unit, and HIF-1β, the constitutive unit. In endometriotic lesions, abnormally high levels of HIF-lα complex have been found, clearly proving that hypoxia is involved in the production of VEGF in endometriosis [46,47].
- IL-10 (interleukin 10), secreted largely by macrophages, is known for inhibiting T cell activation but also for reducing expression of co-stimulatory molecules (CD-80 and CD-86) and indoleamine 2,3-dioxygenase. Interestingly, macrophages secrete IL-15 (interleukin 15), a chemoattractant for uNK (uterine natural killer) cells, and downregulate the cytotoxicity of uNK cells [45,46].
- Nerve growth factors (NGF), especially BDNF (Brain-derived neurotrophic factor), are abnormally synthesized and released by activated macrophages, mast cells, NK (natural killer) cells, and leukocytes within endometriotic formations close to sensitive nerve fibers, and in peritoneal fluid. These sensitize or stimulate endings of sensitive nerve fibers, leading to a vicious cycle characterized by nociceptor sensitization, focal neoneurogenesis, and activation of sensitive nerve fibers, resulting in hyperalgesia [47].
1.2. Objectives
2. Materials and Methods
- Patients who did not freely express their consent for enrollment in the study.
- Patients who did not meet the necessary conditions for study enrollment or who did not attend scheduled follow-up visits as per the protocol.
- A form containing general data, family and personal medical history, symptomatology
- Questionnaire regarding the physical activity practiced by the patient.
- BSGE questionnaire and FSFI questionnaire.
2.1. Analysis of Patient Symptoms and Endometriosis Severity
- Unaffected,
- The patient trying to conceive for less than 18 months without success, or
- The patient trying to conceive for more than 18 months without success.
2.2. Analysis of Investigated Biomarkers
- IL 8—Elabscience Human IL-8 (Interleukin 8) Elisa kit, catalog no: E-EL-H6008
- IL 10—Elabscience Human IL-10 (Interleukin 10) Elisa kit, catalog no: E-EL-H6154
- VEGF—Elabscience Human VEGF-A (Vascular Endothelial Cell Growth Factor A) ELISA kit, catalog no: E-EL-H0111
- BDNF—Elabscience Human BDNF (Brain-Derived Neurotrophic Factor) ELISA kit, catalog No: E-EL-H0010.
2.3. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Expression of Biomarkers at Serum and Tissue Levels
- Uterine fibroid: exhibits elevated IL-8 values similar to endometriosis, with a similar trend for IL-10 but less elevated tissue values compared to endometriosis, higher BDNF values in both serum and tissue and lower serum VEGF-A values but higher tissue values.
- Non-endometriotic ovarian cyst: tissue expression of IL-8 and IL-10 had significantly lower values in cases of non-endometriotic ovarian cysts (43.15 vs. 114.36 pg/mL and 29.53 vs. 71.88 pg/mL, respectively). Regarding BDNF and VEGF-A, only the latter showed higher tissue values.
- Mature ovarian teratoma: shows reduced tissue values of IL-8 and IL-10 but higher values for BDNF and VEGF-A.
3.3. Results of BSGE Questionnaire
3.4. Correlation and Regression of Severity Determinants in Endometriosis
3.5. Analysis of Correlations between IL-8, IL-10 and the Severity of Endometriosis
3.6. Analysis of Linear Regression of Patient-Reported Pain and Physical Activity on Severity of Endometriosis
4. Discussion
- The relatively small number of patients in the two study groups
- The sample of patients exclusively of the Caucasian race
- The heterogeneity of the control group
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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IL-8 S 2 | IL 8-T 3 | IL 10-S 2 | IL-10 T 3 | BDNF S 2 | BDNF T 3 | VEGF-A S 2 | VEGF-A T 3 | |
---|---|---|---|---|---|---|---|---|
average | 37.85 | 114.36 | 34.77 | 71.88 | 784.60 | 53.80 | 243.12 | 43.94 |
Std. dev. 1 | 36.93 | 39.5 | 20.75 | 20.69 | 505.77 | 25.32 | 185.53 | 19.86 |
IL-8 S 2 | IL-8 T 3 | IL-10 S 2 | IL-10 T 3 | BDNF S 2 | BDNF T 3 | VEGF-A S 2 | VEGF-A T 3 | |
---|---|---|---|---|---|---|---|---|
average | 34.73 | 56.95 | 33.41 | 34.34 | 958.60 | 65.96 | 314.04 | 148.33 |
Std. dev. 1 | 42.02 | 54.28 | 18.84 | 15.65 | 639.74 | 48.85 | 378.49 | 120.44 |
IL 8 S 1 | IL 8 T 2 | IL 10 S 1 | IL 10 T 2 | BDNF S 1 | BDNF T 2 | VEGF-A S 1 | VEGF-A T 2 | |
---|---|---|---|---|---|---|---|---|
uterine leiomyoma | 36.42 | 100.99 | 37.97 | 48.89 | 994.31 | 99.05 | 167.81 | 240.58 |
non-endometriotic ovarian cyst | 33.76 | 43.15 | 34.41 | 29.53 | 901.01 | 76.47 | 318.86 | 114.04 |
mature ovarian teratoma | 25.29 | 32.91 | 37.57 | 23.78 | 1108.15 | 42.01 | 402.82 | 87.06 |
uterine septum | 17.79 | 26.61 | 20.32 | 26.74 | 1215.63 | 70.78 | 215.19 | 97.67 |
Coef. | Std. Err. | p-Value | Coef. | Std. Err. | p-Value | |
---|---|---|---|---|---|---|
IL-8_S | −0.027 | 0.036 | 0.464 | |||
IL-8_T | *** 0.065 | 0.021 | 0.003 | *** 0.082 | 0.025 | 0.002 |
IL-10_S | 0.035 | 0.065 | 0.591 | |||
IL-10_T | *** 0.094 | 0.032 | 0.005 | ** 0.087 | 0.038 | 0.029 |
BDNF_S | 0.001 | 0.001 | 0.388 | |||
BDNF_T | −0.017 | 0.023 | 0.469 | |||
VEGF_S | −0.002 | 0.003 | 0.452 | |||
VEGF_T | 0.042 | 0.030 | 0.175 | |||
FSFI | ** −0.753 | 0.290 | 0.013 | ** 0.655 | 0.317 | 0.047 |
AVG_PAIN | *** 2.310 | 0.587 | <0.001 | *** 2.239 | 0.639 | 0.001 |
PROG_COC | *** −3.370 | 1.049 | 0.003 | ** −2.760 | 1.198 | 0.028 |
AGE | 0.122 | 0.077 | 0.120 | 0.168 | 0.103 | 0.112 |
BMI | 0.061 | 0.113 | 0.592 | −0.074 | 0.140 | 0.602 |
SPORT_PHACT | ** −1.243 | 0.589 | 0.042 | ** −1.682 | 0.718 | 0.026 |
n = 46; Adj. R2 = 0.907 n = 46; Adj. R2 = 0.907 |
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Nati, I.D.; Malutan, A.; Ciortea, R.; Oancea, M.; Bucuri, C.; Roman, M.; Ormindean, C.; Milon, A.G.; Mihu, D. Exploring the Influence of IL-8, IL-10, Patient-Reported Pain, and Physical Activity on Endometriosis Severity. Diagnostics 2024, 14, 1822. https://doi.org/10.3390/diagnostics14161822
Nati ID, Malutan A, Ciortea R, Oancea M, Bucuri C, Roman M, Ormindean C, Milon AG, Mihu D. Exploring the Influence of IL-8, IL-10, Patient-Reported Pain, and Physical Activity on Endometriosis Severity. Diagnostics. 2024; 14(16):1822. https://doi.org/10.3390/diagnostics14161822
Chicago/Turabian StyleNati, Ionel Daniel, Andrei Malutan, Razvan Ciortea, Mihaela Oancea, Carmen Bucuri, Maria Roman, Cristina Ormindean, Alexandra Gabriela Milon, and Dan Mihu. 2024. "Exploring the Influence of IL-8, IL-10, Patient-Reported Pain, and Physical Activity on Endometriosis Severity" Diagnostics 14, no. 16: 1822. https://doi.org/10.3390/diagnostics14161822