IMMUNE DYSREGULATION IN PREECLAMPSIA: DIFFERENTIAL EXPRESSION OF TUMOUR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-10 AND THEIR ASSOCIATION WITH CLINICAL, LABORATORY, AND PERINATAL OUTCOMES
DOI:
https://doi.org/10.22159/ajpcr.2025v18i12.56976Keywords:
Preeclampsia, Early-onset preeclampsia, Late-onset preeclampsia, Tumor necrosis factor-alpha, Interleukin-10Abstract
Objective: Preeclampsia (PE) is a multifactorial hypertensive disorder of pregnancy characterized by systemic inflammation and endothelial dysfunction. Aberrant immune responses, particularly an imbalance between pro-inflammatory and anti-inflammatory cytokines, have been implicated in their pathogenesis. This study evaluated the expression of tumor necrosis factor-alpha (TNF-á) and interleukin-10 (IL-10) in earlyonset PE (EOPE) and late-onset PE (LOPE) compared with normotensive pregnancies, and examined their correlation with clinical, laboratory, andperinatal outcomes.
Methods: A total of 200 pregnant women were recruited, including EOPE (n=50), LOPE (n=50), and healthy controls (n=100). Demographic, clinical, and laboratory parameters were recorded. Quantitative real-time polymerase chain reaction was used to assess messenger RNA expression of TNF-á and IL-10 in peripheral blood samples. Statistical analyses included analysis of variance with post hoc testing, Pearson’s correlation, and regression modeling.
Results: EOPE and LOPE groups demonstrated significantly higher systolic and diastolic blood pressures (BP) and proteinuria compared with controls (p<0.001). TNF-á expression was markedly upregulated in EOPE compared with LOPE and controls (p<0.001), whereas IL-10 expression was significantly downregulated in both PE groups (p<0.01). The TNF-á/IL-10 ratio was highest in EOPE, reflecting a pronounced pro-inflammatory shift. Correlation analysis revealed that TNF-á positively correlated with BP, proteinuria, and adverse perinatal outcomes, while IL-10 levels negatively correlated with these parameters. Composite analysis integrating molecular and clinical data reinforced the stronger immune dysregulation in EOPE compared with LOPE.
Conclusion: This study highlights a distinct immunological profile in PE characterized by elevated TNF-á, reduced IL-10, and an exaggerated TNF-á/IL-10 ratio, particularly in EOPE. These findings underscore the role of immune imbalance in disease severity and suggest that cytokine profiling may serve as a potential biomarker and therapeutic target in PE management.
Downloads
References
1. Chang KJ, Seow KM, Chen KH. Preeclampsia: Recent advances in predicting, preventing, and managing the maternal and fetal life-threatening condition. Int J Environ Res Public Health. 2023 Feb 08;20(4):2994. doi: 10.3390/ijerph20042994, PMID 36833689
2. Koulouraki S, Paschos V, Pervanidou P, Christopoulos P, Gerede A, Eleftheriades M. Short- and long-term outcomes of preeclampsia in offspring: Review of the literature. Children (Basel). 2023 May 01;10(5):826. doi: 10.3390/children10050826, PMID 37238374
3. Vera-Ponce VJ, Loayza-Castro JA, Ballena-Caicedo J, Valladolid- Sandoval LA, Zuzunaga-Montoya FE, Gutierrez De Carrillo CI. Global prevalence of preeclampsia, eclampsia, and HELLP syndrome: A systematic review and meta-analysis. Front Reprod Health. 2025 Nov 10;7:1706009. doi: 10.3389/frph.2025.1706009, PMID 41293035
4. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, challenges, and perspectives. Circ Res. 2019 Mar 28;124(7):1094-112. doi: 10.1161/circresaha.118.313276, PMID 30920918
5. Yang M, Wang M, Li N. Advances in pathogenesis of preeclampsia. Arch Gynecol Obstet. 2024 Feb 29;309(5):1815-23. doi: 10.1007/ s00404-024-07393-6, PMID 38421424
6. Possomato-Vieira JS, Khalil RA. Mechanisms of endothelial dysfunction in hypertensive pregnancy and preeclampsia. Adv Pharmacol. 2016 Jan 01;77:361-431. doi: 10.1016/bs.apha.2016.04.008, PMID 27451103
7. Stefańska K, Zieliński M, Jankowiak M, Zamkowska D, Sakowska J, Adamski P, et al. Cytokine imprint in preeclampsia. Front Immunol. 2021 Jun 23;12:667841. doi: 10.3389/fimmu.2021.667841, PMID 34248946
8. Pinheiro MB, Martins-Filho OA, Mota AP, Alpoim PN, Godói LC, Silveira AC, et al. Severe preeclampsia goes along with a cytokine network disturbance towards a systemic inflammatory state. Cytokine. 2013 Mar 21;62(1):165-73. doi: 10.1016/j.cyto.2013.02.027, PMID 23523008
9. Wardhani MK, Gondo HK. Exploring cytokine levels in pregnancy, preeclampsia, and sepsis-complicated preeclampsia. Qanun Med. 2024 Jul 15;8(2):319-29. doi: 10.30651/jqm.v8i02.20427
10. Aronow WS. Hypertensive disorders in pregnancy. Ann Transl Med. 2017 Jul 1;5(12):266. doi: 10.21037/atm.2017.03.104, PMID 28706934
11. Xiang C, Sui L, Ding X, Cao M, Li G, Du Z. Maternal adiposity measures and hypertensive disorders of pregnancy: A meta-analysis. BMC Pregnancy Childbirth. 2024 Oct 16;24(1):675. doi: 10.1186/ s12884-024-06788-2, PMID 39415166
12. Weitzner O, Yagur Y, Weissbach T, Man El GM, Biron-Shental T. Preeclampsia: Risk factors and neonatal outcomes associated with early- versus late-onset diseases. J Matern Fetal Neonatal Med. 2018 Jul 13;33(5):780-4. doi: 10.1080/14767058.2018.1500551, PMID 30001660
13. Huang Y, Sun Q, Zhou B, Peng Y, Li J, Li C, et al. Lipidomic signatures in patients with early-onset and late-onset Preeclampsia. Metabolomics. 2024 Jun 16;20(4):65. doi: 10.1007/s11306-024-02134-x, PMID 38879866
14. Stordeur P. Methods to Quantify Cytokine Gene Expression by Real- Time PCR. Berlin: Springer; 2004. p. 83-92. doi: 10.1007/978-3-642- 18840-4_9
15. Markova AD, Nikolovska K, Aleksievska I, Girevski V, Joksimovikj M. Biochemical indicators as predictive markers by combining clinical signs in pre-eclampsia. Open Access Maced J Med Sci. 2020 Sep 25;8(B):692-8. doi: 10.3889/oamjms.2020.5405
16. Bansal P, Shaker IA, Bansal AK, Kaushik G. Assessment of inflammatory markers in preeclampsia. Indian J Med Biochem. 2018 Jan 01;22(2):138-42. doi: 10.5005/jp-journals-10054-0071
17. Lau SY, Guild SJ, Barrett CJ, Chen Q, McCowan L, Jordan V, et al. Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: Asystematic review and meta-analysis. Am J Reprod Immunol. 2013 Jun 01;70(5):412-27. doi: 10.1111/aji.12138, PMID 23790133
18. Szarka A, Rigó J Jr., Lázár L, Bekő G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 2010 Dec 01;11(1):59. doi: 10.1186/1471-2172-11-59, PMID 21126355
19. Boij R, Berg G, Ernerudh J, Nilsson-Ekdahl K, Svensson J, Sandholm K, et al. Biomarkers of coagulation, inflammation and angiogenesis are independently associated with preeclampsia. J Reprod Immunol. 2012 Apr 28;94(1):109. doi: 10.1016/j.jri.2012.03.447
20. Jarmund AH, Giskeødegård GF, Ryssdal M, Steinkjer B, Stokkeland LM, Madssen TS, et al. Cytokine patterns in maternal serum from first trimester to term and beyond. Front Immunol. 2021 Oct 14;12:752660. doi: 10.3389/fimmu.2021.752660, PMID 34721426
21. Cunningham MW, Jayaram A, Deer E, Amaral LM, Vaka VR, Ibrahim T, et al. Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia. Hypertens Pregnancy. 2020 Jul 10;39(4):399-404. doi: 10.1080/10641955.2020.1793999, PMID 32646252
22. Azizieh FY, Raghupathy RG. Tumor necrosis factor-α and pregnancy complications: A prospective study. Med Princ Pract. 2014 Dec 05;24(2):165-70. doi: 10.1159/000369363, PMID 25501617
23. Romanowska-Próchnicka K, Felis-Giemza A, Olesińska M, Wojdasiewicz P, Paradowska-Gorycka A, Szukiewicz D. The role of TNF-α and Anti-TNF-α agents during preconception, pregnancy, and breastfeeding. Int J Mol Sci. 2021 Mar 13;22(6):2922. doi: 10.3390/ ijms22062922, PMID 33805757
24. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Llurba E, Gris JM. Tumor necrosis factor-alpha and pregnancy: Focus on biologics. An updated and comprehensive review. Clin Rev Allergy Immunol. 2017 Jan 04;53(1):40-53. doi: 10.1007/s12016-016-8596-x, PMID 28054230
25. Broekhuizen M, Hitzerd E, Van Den Bosch TP, Dumas J, Verdijk RM, Van Rijn BB, et al. The placental innate immune system is altered in early-onset preeclampsia, but not in late-onset preeclampsia. Front Immunol. 2021 Dec 21;12:780043. doi: 10.3389/fimmu.2021.780043, PMID 34992598
26. Fei H, Lu X, Shi Z, Liu X, Yang C, Zhu X, et al. Preeclampsia-Specific Immune Cell Network in Placenta Revealed by Cytometry by Time of Flight and Single-Cell RNA-Seq [Preprint]; 2024 Sep 11. p. RP100002. doi: 10.7554/elife.100002.1
27. Ng LF, Chow A, Sun YJ, Kwek DJ, Lim PL, Dimatatac F, et al. IL- 1beta, IL-6, and RANTES as biomarkers of chikungunya severity. PLoS One. 2009 Jan 21;4(1):e4261. doi: 10.1371/journal.pone.0004261, PMID 19156204
28. Katar M, Onder Y, Citil R, Demir O, Yigit T. Comparison of inflammation markers in different severities of Covid-19 disease. Int J Med Biochem. 2021 Jan 01;5:34-43. doi: 10.14744/ijmb.2021.39358
29. Chong AS, Sage PT, Alegre ML. Regulation of alloantibody responses. Front Cell Dev Biol. 2021 Jul 08;9:706171. doi: 10.3389/ fcell.2021.706171, PMID 34307385
30. Poznansky SA, Yu M, Deng K, Fu Q, Markmann JF, LeGuern C. Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation. Front Immunol. 2023 Apr 27;14:1173672. doi: 10.3389/fimmu.2023.1173672, PMID 37180165
31. Garrido-Giménez C, Cruz-Lemini M, Álvarez FV, Nan MN, Carretero F, Fernández-Oliva A, et al. Predictive model for preeclampsia combining sFlt-1, PlGF, NT-proBNP, and uric acid as biomarkers. J Clin Med. 2023 Jan 05;12(2):431. doi: 10.3390/jcm12020431, PMID 36675361
32. Nunes PR, Romão-Veiga M, Borges VT, Matias ML, Ribeiro VR, Costa RA, et al. Association between adverse maternal clinical outcomes and imbalance of cytokines and angiogenic factors in preterm preeclampsia. Rev Bras Ginecol Obstet. 2021 Sep 01;43(9):669-75. doi: 10.1055/s-0041-1735157, PMID 34670301
Published
How to Cite
Issue
Section
Copyright (c) 2025 POGULA ASHALATHA, SRIKANTH TOKALI, KALAKANTI SHWETA, MUTHULAKSHMI R, ASHOK VARDHAN N

This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.