SIGNIFICANCE OF THE RELATIONSHIP BETWEEN PROINFLAMMATORY CYTOKINE GENE POLYMORPHISMS AND PITUITARY FOLLICULOSTELLATE CELLS FOR HUMAN LONGEVITY
Keywords:
aging; cadavers; folliculostellate cells; TNF-α, IL-1β, IL-6
Abstract
Background: The focus of this study was on the analysis of the relationships between polymorphisms of proinflammatory cytokine genes (tumor necrosis factor α-TNF-α; interleukin 6-IL-6; and interleukin1β-IL-1β), morphology of non-endocrine pituitary folliculostellate cells (FS), gender, and age.
Methods: The research involved 20 cadavers (10 male and 10 female) divided into two groups: from 51 to 70 years of age (group I) and over 70 years of age (group II). Pituitary glands were collected during routine autopsy. Isolated pituitaries of cadavers of both sexes were prepared using routine histological techniques. On 5-µm-thick pituitary sections, FS cells were immunohistochemically stained using primary polyclonal anti-S100 (1:400) antibody, visualized by DAB, and analyzed by light microscopy at 40x magnification. Stereological analysis was performed using the ImageJ program. The PCR-RFLP method was used for the genotyping of single nucleotide polymorphisms (SNPs) of TNFα, IL-1β and IL-6.
Results: The morphology of FS cells in the second age group showed that they were irregularly shaped, more numerous, single or in groups and significantly (p˂0.05) larger (2.23 times) compared to group I. Single nucleotide polymorphism (SNP) analysis showed no correlation between SNPs of the examined genes and FS cell morphology.
Conclusions: It was concluded that in humans of both genders the volume density of FS cells increases with age and is not related to gene polymorphisms of TNFα, IL-1β and IL-6.
References
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32. Čukuranović-Kokoris J, Kundalić B, Pavlović M, Ugrenović S. Pituitary cells in man during aging: an immunohistological and morphometric study. J Med Biochem 2025; 44(2): 203-10. DOI: 10.5937/jomb0-54605
33. Morris J, Christian H. Folliculo-stellate cells: paracrine communicators in the anterior pituitary. Neuroendocrinol J 2011; 4: 77-89. DOI: 10.2174/1876528901104010077
34. Beburishvili AG, Burchuladze NS, Mikhin VS, Kitaeva AV, Mikhin IV. Prediction and diagnosis of pancreatogenic encephalopathy in patients with destructive pancreatitis. Khirurgiia (Mosk) 2022; 7: 58-63. DOI: 10.17116/hirurgia202207158
35. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg JV, Pedersen BK. Jeune B. Elevated levels of tumour necrosis factor-alpha and mortality in centenarians. Am J Med 2003; 115: 278-83. DOI: 10.1016/s0002-9343(03)00329-2
36. Wang T. TNF-alpha G308A polymorphism and the susceptibility to Alzheimer’s disease: an updated meta-analysis. Arch Med Res 2015; 46(1): 24-30e1. DOI: 10.1016/j.arcmed.2014.12.006
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39. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in Aging and Chronic Disease: A Magnificent Pathway J Gerontol A Biol Sci Med Sci 2006; 61A(6): 575–84. DOI: 10.1093/gerona/61.6.575
40. YuqY, Lan Z, Huang Z, Hu L. Correlation analysis of serum cytokine levels and immune
Inflammatory factors in cirrhotic portal hypertension. J Med Biochem 2026; 45(4): 882–8.
DOI: 10.5937/jomb0-60996
41. Soerensen M, Dato S, Tan Q, Thinggaard M, Kleindorp R, Beekman M, Suchiman HE, Jacobsen R, McGue M, Stevnsner T, Bohr VA, de Craen AJ, Westendorp RG, Schreiber S, Slagboom PE, Nebel A, Vaupel JW, Christensen K, Christiansen L. Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age 2013; 35(2): 487–500. DOI: 10.1007/s11357-011-9373-7
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2. Vennekens A, Laporte E, Hermans F, Cox B, Modave E, Janiszewski A, Nys C, Kobayashi H, Malengier-Devlies B, Chappell J, Matthys P, Garcia MI, Pasque V, Lambrechts D, Vankelecom H. Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland. Proc Natl Acad Sci U S A 2021; 118(25): e2100052118. DOI: 10.1073/pnas.2100052118
3. Bauer ME, Wieck A, Petersen LE, Baptista TS. Neuroendocrine and viral correlates of premature immunosenescence. Ann N Y Acad Sci 2015; 1351:11-21. DOI: 10.1111/nyas.12786
4. Rea IM, Gibson DS, McGilliga V, McNerlan SE, Alexander HD, Ross, OA. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 2018; 9: 586. DOI: 10.3389/fimmu.2018.00586
5. Tylutka A, Walas Ł, Zembron-Lacny A. Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis. Front Immunol 2024; 15: 1330386. DOI: 10.3389/fimmu.2024.1330386
6. Pavlović M, Jovanović I, Ugrenović S, Vasović L, Krstić M, Bakić M, Živković V, Stojanović V. Morphometric analysis of the human anterior pituitary’s folliculostellate cells during the aging process. Ann Anat 2013; 195(3): 231-7. DOI: 10.1016/j.aanat.2012.11.002
7. Le Tissier PR, Mollard P. Renewing an old interest: Pituitary folliculostellate cells. J Neuroendocrinol 2021; 33(11): e13053. DOI: 10.1111/jne.13053
8. Cimini V, Van Noorden S, Terlizzi C, Altobelli GG. Calcium/calmodulin-dependent kinases in the hypothalamus, pituitary, and pineal gland: an overview. Int J Endocrinol 2022; 2022: 1103346. DOI: 10.1155/2022/1103346
9. Sandrah N. Narrative review of anti-inflammatory phytochemicals. IDOSR Journal of Applied Sci 2025; 10(3): 149-58. DOI: 10.59298/IDOSRJAS/2025/103.149158
10. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997; 94: 3195-9. DOI: 10.1073/pnas.94.7.3195
11. Clerici M, Arosio B, Mundo E, Cattaneo E, Pozzoli S, Dell'osso B, Vergani C, Trabattoni D, Altamura AC. Cytokine polymorphisms in the pathophysiology of mood disorders. CNS Spectr 2009; 14: 419-25. DOI: 10.1017/s1092852900020393
12. Dinarello CA, Charles A. Interleukin-1 family. In: Thomson AW and Lotze MT (eds) The cytokine Hand-book, Academic Press Inc, Avon, 2003, pp. 643-68.
13. Lima TS. Beyond an inflammatory mediator: Interleukin-1 in neurophysiology. Exp Physio 2023; 108(7): 917-24. DOI: 10.1113/EP090780
14. Lind H, Haugen A, Zienolddiny S. Differential binding of proteins to the IL1B–31 T/C polymorphism in lung epithelial cells. Cytokine 2007; 38: 43-8. DOI: 10.1016/j.cyto.2007.05.001
15. Hakim J, Khan AR, Jian A. Type III hyperlipoproteinemia. Clin Cardiol 2002; 25(4): 193. DOI: 10.1002/clc.4960250411
16. Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol 2023; 14: 1255533. DOI: 10.3389/fimmu.2023.1255533
17. Woo P, Humphries SE. IL-6 polymorphisms: a useful genetic tool for inflammation research? J Clin Invest 2013; 123(4): 1413-4. DOI: 10.1172/JCI67221
18. Hao Y, Zhou Q, Sun Y, Niu W, Du J. Association of three single nucleotide polymorphisms in interleukin 6 gene with risk of chronic obstructive pulmonary disease. Gene 2022; 828: 146467. DOI: 10.1016/j.gene.2022.146467
19. Posadas-Sánchez R, López-Uribe, ÁR, Fragoso JM, Vargas-Alarcón G. Interleukin 6 polymorphisms are associated with cardiovascular risk factors in premature coronary artery disease patients and healthy controls of the GEA Mexican study. Exp Mol Pathol 2024; 136: 104886. DOI: 10.1016/j.yexmp.2024.104886
20. Cui ZH, Lu XT, Xiao KL, Chen Y, Li, HQ. Association of interleukin-6 -174G/C polymorphism with the risk of diabetic nephropathy in type 2 diabetes: a meta-analysis. Curr Med Sci 2019; 39(2): 250-8. DOI: 10.1007/s11596-019-2027-1
21. Bojarczuk A, Garbacz A, Żekanowski C, Borzemska B, Cięszczyk P, Maculewicz E. Systematic review of IL-1, IL-4, IL-6, IL-10, IL-15, and IL-18 gene polymorphisms and meta-analysis of IL-6 variant and its association with overweight and obesity risk in men. Int J Mol Sci 2024; 25(24): 13501. DOI: 10.3390/ijms252413501
22. Capurso C, Solfrizzi V, Colacicco AM, D'Introno A, Frisardi V, Imbimbo BP, Lorusso M, Vendemiale G, Denitto M, Santamato A, Seripa D, Pilotto A, Fiore P, Capurso A, Panza F. Interleukin 6-174 G/C promoter and variable number of tandem repeats (VNTR) gene polymorphisms in sporadic Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(1): 177-82. DOI: 10.1016/j.pnpbp.2009.10.022
23. Čukuranović-Kokoris J, Jovanović I, Ugrenović S, Stojanović V, Pavlović M, Kundalić B, Živković V, Antić M, Čukuranović R. Immunohistochemical and morphometric study of adenohypophyseal gonadotropic cells in male cadavers of different ages. Acta Medica Medianae 2020; 59(4): 49-61. DOI: 10.5633/amm.2020.0407
24. Čukuranović-Kokoris J, Jovanović I, Pantović V, Krstić M, Stanojković M, Milošević V, Ugrenović S, Stojanović V. Morphometric analysis of the folliculostellate cells and luteinizing hormone gonadotropic cells of the anterior pituitary of the men during the aging process. Tissue Cell 2017; 49(1): 78-85. DOI: 10.1016/j.tice.2016.11.006
25. Čukuranović-Kokoris J, Đorđević M, Jovanović I, Kundalić B, Pavlović M, Graovac I, Ajdžanović V, Ristić N, Marković-Filipović J, Milošević V. Morphometric analysis of somatotropic and folliculostellate cells of human anterior pituitary during ageing. Srp Arh Celok Lek 2022; 150(5-6): 274-81. DOI: 10.2298/SARH211214044C
26. El Gendy F, El-Mekkawy SM, El-Naidany SS, Shimaa Tarek El-TorgomanTS. The role of Tumor necrosis factor alpha-308 G>A promoter polymorphism in pediatric community acquired pneumonia. Egyptian Pediatric Association Gazette 2020; 68(5): 1-7. DOI: 10.1186/s43054-020-0019-1
27. Soto-López JD, García-Martín JM, Lizana-Ciudad D, Lizana M, Hernández-Tabernero L, Fernández-Soto P, Velásquez-González OE, Aragón SL, Belhassen-García M, Muro A Taxonomic and functional profiling of bat guano microbiota from hiking trail-associated tunnels: a potential risk for human health? Environ Microbiome. 2025; 20(1): 123. DOI: 10.1186/s40793-025-00782-7.
28. Márquez-Coello M, Montes-de-Oca Arjona M, Fernández-Gutiérrez del Álamo C, Ruiz-Sánchez C, Girón-González JA. Peripheral Th17 cells expressing β7 intestinal homing receptor in recent and chronic HIV infections. Clin Exp Immunol 2018; 194 (3): 350–60. DOI: 10.1111/cei.13201
29. Stankovic S, Mutavdzin-Krneta S, Djuric D, Milosevic V, Milenkovic D. Plant polyphenols as heart’s best friends: from health properties, to cellular effects, to molecular mechanisms of action. J Mol Sci 2025; 26: 915. DOI: 10.3390/ijms26030915
30. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007; 128(1): 92-105. DOI: 10.1016/j.mad.2006.11.016
31. Jovanović I, Ugrenović S, Ljubomirović M, Vasović L,Čukuranović R, Stefanović V. Folliculo-stellate cells - potential mediators of the inflammaging-induced hyperactivity of the hypothalamic-pituitary-adrenal axis in healthy elderly individuals. Med Hypotheses 2014; 83(4): 501-5. DOI: 10.1016/j.mehy.2014.08.018
32. Čukuranović-Kokoris J, Kundalić B, Pavlović M, Ugrenović S. Pituitary cells in man during aging: an immunohistological and morphometric study. J Med Biochem 2025; 44(2): 203-10. DOI: 10.5937/jomb0-54605
33. Morris J, Christian H. Folliculo-stellate cells: paracrine communicators in the anterior pituitary. Neuroendocrinol J 2011; 4: 77-89. DOI: 10.2174/1876528901104010077
34. Beburishvili AG, Burchuladze NS, Mikhin VS, Kitaeva AV, Mikhin IV. Prediction and diagnosis of pancreatogenic encephalopathy in patients with destructive pancreatitis. Khirurgiia (Mosk) 2022; 7: 58-63. DOI: 10.17116/hirurgia202207158
35. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg JV, Pedersen BK. Jeune B. Elevated levels of tumour necrosis factor-alpha and mortality in centenarians. Am J Med 2003; 115: 278-83. DOI: 10.1016/s0002-9343(03)00329-2
36. Wang T. TNF-alpha G308A polymorphism and the susceptibility to Alzheimer’s disease: an updated meta-analysis. Arch Med Res 2015; 46(1): 24-30e1. DOI: 10.1016/j.arcmed.2014.12.006
37. Jarczak, D, Nierhaus, A. Cytokine storm-definition, causes, and implications. Int J Mol Sci 2022; 23(19), 11740. DOI: 10.3390/ijms231911740
38. Bonafè M, Olivieri F, Cavallone L, Giovagnetti S, Mayegiani F, Cardelli M, Pieri C, Marra M, Antonicelli R, Lisa R, Rizzo MR, Paolisso G, Monti D, Franceschi C. A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol 2001; 31: 2357-61. DOI: 10.1002/1521-4141(200108)31:8<2357::aid-immu2357>3.0.co;2-x
39. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in Aging and Chronic Disease: A Magnificent Pathway J Gerontol A Biol Sci Med Sci 2006; 61A(6): 575–84. DOI: 10.1093/gerona/61.6.575
40. YuqY, Lan Z, Huang Z, Hu L. Correlation analysis of serum cytokine levels and immune
Inflammatory factors in cirrhotic portal hypertension. J Med Biochem 2026; 45(4): 882–8.
DOI: 10.5937/jomb0-60996
41. Soerensen M, Dato S, Tan Q, Thinggaard M, Kleindorp R, Beekman M, Suchiman HE, Jacobsen R, McGue M, Stevnsner T, Bohr VA, de Craen AJ, Westendorp RG, Schreiber S, Slagboom PE, Nebel A, Vaupel JW, Christensen K, Christiansen L. Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age 2013; 35(2): 487–500. DOI: 10.1007/s11357-011-9373-7
42. Boraschi D. What Is IL-1 for? The Functions of Interleukin-1 Across Evolution Front Immunol 2022; 13:872155. DOI: 10.3389/fimmu.2022.872155
43. Cederholm T, Persson M, Andersson P, Stenvinkel P, Nordfors L, Madden J, Vedin I, Wretlind B, Grimble RF, Palmblad J. Polymorphisms in cytokine genes influence long-term survival differently in elderly male and female patients. J Intern Med 2007; 262: 215-23. DOI: 10.1111/j.1365-2796.2007.01803.x
44. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11(8): 633-52. DOI: 10.1038/nrd3800
Published
2026/05/25
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