Hypoxic MSCs Secretome Modulates IL-18-Mediated Inflammatory in Type 2 Diabetes Mellitus via AP-1 Regulation
Keywords:
AP-1, Hypoxic MSCs, IL-18, Secretome, T2DM
Abstract
Background: Chronic inflammation is central to the pathophysiology of Type 2 Diabetes Mellitus (T2DM), contributing to the progression of metabolic dysfunction characterized by hyperglycaemia and insulin resistance. This study aims to investigate the therapeutic potential of the hypoxic MSCs secretome (SH-MSCs) in reducing inflammation of a T2DM rat model. Methods: T2DM was induced in Wistar rats through a high-fat diet (HFD) followed by streptozotocin (STZ) administration. A total of 24 healthy male Wistar rats were randomly assigned to five groups: healthy control, T2DM, T2DM + metformin, T2DM + SH-MSCs. Results: SH-MSCs significantly reduced IL-18 mRNA expression, a key indicator of proinflammation, and suppressed the expression of AP-1 mRNA, a crucial proinflammatory transcription factor. Conclusion: These findings highlight the therapeutic potential of SH-MSCs as an alternative approach to alleviate inflammation in T2DM.
References
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29. Piaszyk-Borychowska A, Széles L, Csermely A, Chiang HC, Wesoły J, Lee CK, et al. Signal Integration of IFN-I and IFN-II With TLR4 Involves Sequential Recruitment of STAT1-Complexes and NFκB to Enhance Pro-inflammatory Transcription. Front Immunol. 2019;10:1253.
30. Hu X, Chakravarty SD, Ivashkiv LB. Regulation of IFN and TLR Signaling During Macrophage Activation by Opposing Feedforward and Feedback Inhibition Mechanisms. Immunol Rev. 2008 Dec;226:41–56.
31. Ge J, Yan Q, Wang Y, Cheng X, Song D, Wu C, et al. IL-10 delays the degeneration of intervertebral discs by suppressing the p38 MAPK signaling pathway. Free Radic Biol Med. 2020 Feb 1;147:262–70.
32. Pua LJW, Mai CW, Chung FFL, Khoo ASB, Leong CO, Lim WM, et al. Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma. Int J Mol Sci. 2022 Jan 20;23(3):1108.
33. Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med. 2020 Mar 1;19(3):1997–2007.
34. Duncan SA, Sahu R, Dixit S, Singh SR, Dennis VA. Suppressors of Cytokine Signaling (SOCS)1 and SOCS3 Proteins Are Mediators of Interleukin-10 Modulation of Inflammatory Responses Induced by Chlamydia muridarum and Its Major Outer Membrane Protein (MOMP) in Mouse J774 Macrophages. Mediators Inflamm. 2020;2020(1):7461742.
35. Cevey ÁC, Penas FN, Alba Soto CD, Mirkin GA, Goren NB. IL-10/STAT3/SOCS3 Axis Is Involved in the Anti-inflammatory Effect of Benznidazole. Front Immunol. 2019 Jun 4;10:1267.
36. Rothschild DE, McDaniel DK, Ringel-Scaia VM, Allen IC. Modulating Inflammation through the Negative Regulation of NF-κB Signaling. J Leukoc Biol. 2018 Feb 1;10.1002/JLB.3MIR0817-346RRR.
37. Gao Y, Tu D, Yang R, Chu CH, Hong JS, Gao HM. Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1β Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration. Int J Mol Sci. 2020 Jan 11;21(2):465.
38. Liao Y, Fu Z, Huang Y, Wu S, Wang Z, Ye S, et al. Interleukin-18-primed human umbilical cord-mesenchymal stem cells achieve superior therapeutic efficacy for severe viral pneumonia via enhancing T-cell immunosuppression. Cell Death Dis. 2023 Jan 28;14(1):66.
39. Silvia A, Claudia M, Cristina B, Manuel SA, Rigillo G, Blom JM, et al. Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells. Brain Behav Immun. 2014 Aug;40:85–94.
40. Ihim SA, Abubakar SD, Zian Z, Sasaki T, Saffarioun M, Maleknia S, et al. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front Immunol [Internet]. 2022 Aug 11 [cited 2025 Mar 18];13. Available from: https://www.frontiersin.orgundefined/journals/immunology/articles/10.3389/fimmu.2022.919973/full
41. Zhuo Y, Li X, He Z, Lu M. Pathological mechanisms of neuroimmune response and multitarget disease-modifying therapies of mesenchymal stem cells in Parkinson’s disease. Stem Cell Res Ther. 2023 Apr 12;14:80.
42. Xue M, Zhang X, Chen J, Liu F, Xu J, Xie J, et al. Mesenchymal Stem Cell-Secreted TGF-β1 Restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 Suppression. Stem Cells Int. 2022 Mar 12;2022:5522828.
43. Zhang F, Wang H, Wang X, Jiang G, Liu H, Zhang G, et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget. 2016 Jul 13;7(32):52294–306.
2. Panuganti KK, Nguyen M, Kshirsagar RK. Obesity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Mar 14]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK459357/
3. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol - Cell Physiol. 2021 Mar 1;320(3):C375–91.
4. Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2020 Jan 29;10:1607.
5. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol-Cell Physiol. 2021 Mar 1;320(3):C375–91.
6. Peng Y, Zhou M, Yang H, Qu R, Qiu Y, Hao J, et al. Regulatory Mechanism of M1/M2 Macrophage Polarization in the Development of Autoimmune Diseases. Mediators Inflamm. 2023 Jun 8;2023:8821610.
7. Zeke András, Misheva Mariya, Reményi Attila, Bogoyevitch Marie A. JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. Microbiol Mol Biol Rev. 2016 Jul 27;80(3):793–835.
8. Chen S, Saeed AFUH, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther. 2023 May 22;8(1):1–35.
9. Rex DAB, Agarwal N, Prasad TSK, Kandasamy RK, Subbannayya Y, Pinto SM. A comprehensive pathway map of IL-18-mediated signalling. J Cell Commun Signal. 2020 Jun;14(2):257–66.
10. Shawki HA, Elzehery R, Shahin M, Abo-hashem EM, Youssef MM. Evaluation of some oxidative markers in diabetes and diabetic retinopathy. Diabetol Int. 2020 Jun 27;12(1):108–17.
11. Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019 Feb 26;10(1):68.
12. Bian D, Wu Y, Song G, Azizi R, Zamani A. The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review. Stem Cell Res Ther. 2022 Jan 24;13(1):24.
13. Sari MI, Jusuf NK, Munir D, Putra A, Bisri T, Ilyas S, et al. The Role of Mesenchymal Stem Cell Secretome in the Inflammatory Mediators and the Survival Rate of Rat Model of Sepsis. Biomedicines. 2023 Aug 21;11(8):2325.
14. da Silva AV, Serrenho I, Araújo B, Carvalho AM, Baltazar G. Secretome as a Tool to Treat Neurological Conditions: Are We Ready? Int J Mol Sci. 2023 Jan;24(22):16544.
15. Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? J Adv Res [Internet]. 2024 May 9 [cited 2025 Mar 14]; Available from: https://www.sciencedirect.com/science/article/pii/S2090123224001814
16. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci. 2017 Aug 25;18(9):1852.
17. Fardhani IM, Firdaus J, Febianti Z, Hairrudin H, Abrori C, Sakinah EN. THE EFFECT OF NEEM GUM ON THE REDUCTION IN RAT BLOOD GLUCOSE LEVELS INDUCED BY STREPTOZOTOCIN. Bul Vet Udayana. 2023 Jul 23;982.
18. Jiménez-Maldonado A, García-Suárez PC, Rentería I, Moncada-Jiménez J, Plaisance EP. Impact of high-intensity interval training and sprint interval training on peripheral markers of glycemic control in metabolic syndrome and type 2 diabetes. Biochim Biophys Acta BBA - Mol Basis Dis. 2020 Aug 1;1866(8):165820.
19. Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M. Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus. Compr Physiol. 2018 Dec 13;9(1):1–58.
20. Yukawa M, Jagannathan S, Vallabh S, Kartashov AV, Chen X, Weirauch MT, et al. AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation. J Exp Med. 2019 Oct 25;217(1):e20182009.
21. Atsaves V, Leventaki V, Rassidakis GZ, Claret FX. AP-1 Transcription Factors as Regulators of Immune Responses in Cancer. Cancers. 2019 Jul 23;11(7):1037.
22. Dludla PV, Mabhida SE, Ziqubu K, Nkambule BB, Mazibuko-Mbeje SE, Hanser S, et al. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes. 2023 Mar 15;14(3):130–46.
23. Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther. 2024 Mar 4;9(1):1–37.
24. Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY. Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication. Front Oncol. 2019 Feb 21;9:48.
25. Patrick R, Naval-Sanchez M, Deshpande N, Huang Y, Zhang J, Chen X, et al. The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening. Cell Metab. 2024 Aug 6;36(8):1858-1881.e23.
26. Tu YC, Huang DY, Shiah SG, Wang JS, Lin WW. Regulation of c-Fos Gene Expression by NF-κB: A p65 Homodimer Binding Site in Mouse Embryonic Fibroblasts but Not Human HEK293 Cells. PLoS ONE. 2013 Dec 30;8(12):e84062.
27. Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. 2020 Sep 21;5(1):1–23.
28. Ji Z, He L, Regev A, Struhl K. Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers. Proc Natl Acad Sci. 2019 May 7;116(19):9453–62.
29. Piaszyk-Borychowska A, Széles L, Csermely A, Chiang HC, Wesoły J, Lee CK, et al. Signal Integration of IFN-I and IFN-II With TLR4 Involves Sequential Recruitment of STAT1-Complexes and NFκB to Enhance Pro-inflammatory Transcription. Front Immunol. 2019;10:1253.
30. Hu X, Chakravarty SD, Ivashkiv LB. Regulation of IFN and TLR Signaling During Macrophage Activation by Opposing Feedforward and Feedback Inhibition Mechanisms. Immunol Rev. 2008 Dec;226:41–56.
31. Ge J, Yan Q, Wang Y, Cheng X, Song D, Wu C, et al. IL-10 delays the degeneration of intervertebral discs by suppressing the p38 MAPK signaling pathway. Free Radic Biol Med. 2020 Feb 1;147:262–70.
32. Pua LJW, Mai CW, Chung FFL, Khoo ASB, Leong CO, Lim WM, et al. Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma. Int J Mol Sci. 2022 Jan 20;23(3):1108.
33. Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med. 2020 Mar 1;19(3):1997–2007.
34. Duncan SA, Sahu R, Dixit S, Singh SR, Dennis VA. Suppressors of Cytokine Signaling (SOCS)1 and SOCS3 Proteins Are Mediators of Interleukin-10 Modulation of Inflammatory Responses Induced by Chlamydia muridarum and Its Major Outer Membrane Protein (MOMP) in Mouse J774 Macrophages. Mediators Inflamm. 2020;2020(1):7461742.
35. Cevey ÁC, Penas FN, Alba Soto CD, Mirkin GA, Goren NB. IL-10/STAT3/SOCS3 Axis Is Involved in the Anti-inflammatory Effect of Benznidazole. Front Immunol. 2019 Jun 4;10:1267.
36. Rothschild DE, McDaniel DK, Ringel-Scaia VM, Allen IC. Modulating Inflammation through the Negative Regulation of NF-κB Signaling. J Leukoc Biol. 2018 Feb 1;10.1002/JLB.3MIR0817-346RRR.
37. Gao Y, Tu D, Yang R, Chu CH, Hong JS, Gao HM. Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1β Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration. Int J Mol Sci. 2020 Jan 11;21(2):465.
38. Liao Y, Fu Z, Huang Y, Wu S, Wang Z, Ye S, et al. Interleukin-18-primed human umbilical cord-mesenchymal stem cells achieve superior therapeutic efficacy for severe viral pneumonia via enhancing T-cell immunosuppression. Cell Death Dis. 2023 Jan 28;14(1):66.
39. Silvia A, Claudia M, Cristina B, Manuel SA, Rigillo G, Blom JM, et al. Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells. Brain Behav Immun. 2014 Aug;40:85–94.
40. Ihim SA, Abubakar SD, Zian Z, Sasaki T, Saffarioun M, Maleknia S, et al. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front Immunol [Internet]. 2022 Aug 11 [cited 2025 Mar 18];13. Available from: https://www.frontiersin.orgundefined/journals/immunology/articles/10.3389/fimmu.2022.919973/full
41. Zhuo Y, Li X, He Z, Lu M. Pathological mechanisms of neuroimmune response and multitarget disease-modifying therapies of mesenchymal stem cells in Parkinson’s disease. Stem Cell Res Ther. 2023 Apr 12;14:80.
42. Xue M, Zhang X, Chen J, Liu F, Xu J, Xie J, et al. Mesenchymal Stem Cell-Secreted TGF-β1 Restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 Suppression. Stem Cells Int. 2022 Mar 12;2022:5522828.
43. Zhang F, Wang H, Wang X, Jiang G, Liu H, Zhang G, et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget. 2016 Jul 13;7(32):52294–306.
Published
2025-04-26
How to Cite
Amansyah, F., Alif, I., & Irawan, R. C. S. (2025). Hypoxic MSCs Secretome Modulates IL-18-Mediated Inflammatory in Type 2 Diabetes Mellitus via AP-1 Regulation. International Journal of Cell and Biomedical Science, 3(7), 189-200. https://doi.org/10.59278/cbs.v3i7.47
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