The Role of Mesenchymal Stem Cells in Decreasing Interleukin-12 Human Systemic Lupus Erythematosus

Delfitri Munir; Rodiah Rahmawaty Lubis; Dewi Masyithah Darlan; Agung Putra; Iffan Allif

doi:10.3889/oamjms.2020.5120

Authors

Delfitri Munir Pusat Unggulan IPTEK Tissue Engineering, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
Rodiah Rahmawaty Lubis Department of Ophthalmology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
Dewi Masyithah Darlan Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
Agung Putra Stem Cell and Cancer Research (SCCR), Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Department of Postgraduate Biomedical Science, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Department of Pathological Anatomy, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
Iffan Allif Stem Cell and Cancer Research (SCCR),Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang

DOI:

https://doi.org/10.3889/oamjms.2020.5120

Keywords:

MSCs, IL12, Invitro, Human, SLE

Abstract

BACKGROUND: Systemic lupus erythematosus (SLE) disease is characterized by a loss of self-tolerance leading to a local tissue inflammation up to a massive systemic organ-spesific inflammation. Mesenchymal stem cells (MSCs) present immunomodulatory properties to control the over-activating immune responses in SLE through several mechanisms. However, the capability of MSCs to decrease interleukin (IL)-12 production in in vitro remains unclear.

AIM: The aim of this study was to investigate the role of MSCs in decreasing the level of IL-12 derived from peripheral blood mononuclear cells (PBMCs) of SLE patients.

METHODS: This study used a post-test control group design using a coculture of PBMCs from SLE and healthy patients with MSCs as the subjects. This study included five groups: sham (Sh), control (C), and treatment groups (T) treated by a co-culture MSCs with PBMCs at ratio dose of 1:1 (T1), 1:25 (T2), and 1:50 (T3), respectively, for 72 hours of incubation. The IL-12 levels was analysed by cytometric bead array (CBA) of flow cytometry.

RESULTS: This study showed a significant decrease of IL-12 levels (p < 0.05) in T1 and T2 after 72 hours incubation of co-culture MSCs with PBMCs from SLE patient.

CONCLUSION: MSCs could decrease the level of IL-12 in PBMCs of human SLE to control the inflammation of SLE disease.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

Author Biography

Dewi Masyithah Darlan, Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

Parasitology Department, Faculty of Medicine

References

Bertolaccini ML, Sciascia S, Radin M, Roccatello D, Sanna G. Recent advances in the management of systemic lupus erythematosus. F1000Res. 2018;7:1-17. https://doi.org/10.12688/f1000research.13941.1 PMid:30026918

Moulton VR, Suarez-Fueyo A, Meidan E, Li H, Mizui M, Tsokos GC. Pathogenesis of human systemic lupus erythematosus: A cellular perspective. Trends Mol Med. 2017;23(7):615-35. https://doi.org/10.1016/j.molmed.2017.05.006 PMid:28623084

Stojan G, Petri M. Epidemiology of systemic lupus erythematosus: An update. Curr Opin Rheumatol. 2018;30(2):144-50. PMid:29251660

Larosa M, Zen M, Gatto M, Jesus D, Zanatta E, Iaccarino L, et al. IL-12 and IL-23/Th17 axis in systemic lupus erythematosus. Exp Biol Med (Maywood). 2019;244(1):42-51. PMid:30664357

Cheng RJ, Xiong AJ, Li YH, Pan SY, Zhang QP, Zhao Y, et al. Mesenchymal stem cells: Allogeneic MSC may be immunosuppressive but autologous MSC are dysfunctional in lupus patients. Front Cell Dev Biol. 2019;7:1-13. https://doi.org/10.3389/fcell.2019.00285 PMid:31799252

Rastegar F, Shenaq D, Huang J, Zhang W, Zhang BQ, He BC, et al. Mesenchymal stem cells: Molecular characteristics and clinical applications. World J Stem Cells. 2010;2(24):67-80. PMid:21607123

Darlan DM, Munir D, Putra A, Jusuf NK. MSCs-released TGFβ1 generate CD4+CD25+Foxp3+ in T-reg cells of human SLE PBMC. J Formos Med Assoc. 2020;40:1-7. https://doi. org/10.1016/j.jfma.2020.06.028

Ikhsan R, Putra A, Munir D, Darlan DM, Suntoko B, Retno A. Mesenchymal stem cells induce regulatory T-cell population in human SLE. Bangladesh J Med Sci. 2020;19(4):743-8. https://doi.org/10.3329/bjms.v19i4.46635

Luz-Crawford P, Kurte M, Bravo-Alegría J, Contreras R, Nova-Lamperti E, Tejedor G, et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013;4(3):65. https://doi.org/10.1186/scrt216 PMid:23734780

Larosa M, Iaccarino L, Gatto M, Punzi L, Doria A. Advances in the diagnosis and classification of systemic lupus erythematosus. Expert Rev Clin Immunol. 2016;12(12):1309- 20. https://doi.org/10.1080/1744666x.2016.1206470 PMid:27362864

Noble A, Thomas MJ, Michael Kemeny D. Early Th1/Th2 cell polarization in the absence of IL-4 and IL-12: T cell receptor signaling regulates the response to cytokines in CD4 and CD8 T cells. Eur J Immunol. 2001;31(7):2227-35. https://doi.org/10.1002/1521- 4 1 4 1 ( 2 0 0 1 0 7 ) 3 1 :7 < 2 2 2 7 ::a i d - i m m u 2 2 2 7 > 3 .0 .c o ;2 - c PMid:11449377

Nembrini C, Abel B, Kopf M, Marsland BJ. Strong TCR signaling, TLR ligands, and cytokine redundancies ensure robust development of Type 1 effector T cells. J Immunol. 2006;176(12):7180-8. https://doi.org/10.4049/jimmunol.176.12.7180 PMid:16751361

Buckner JH. Mechanisms of impaired regulation by CD4(+) CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12):849-59. https://doi.org/10.1038/nri2889 PMid:21107346

Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3(2):133-46. https://doi.org/10.1038/nri1001 PMid:12563297

Lauwerys BR, Van Snick J, Houssiau FA. Serum IL-12 in systemic lupus erythematosus: Absence of p70 heterodimers but presence of p40 monomers correlating with disease activity. Lupus. 2002;11(6):384-7. https://doi.org/10.1191/0961203302lu213oa PMid:12139377

Miteva LD, Manolova IM, Ivanova MG, Rashkov RK, Stoilov RM, Gulubova MV, et al. Functional genetic polymorphisms in interleukin-12B gene in association with systemic lupus erythematosus. Rheumatol Int. 2012;32(1):53-9. https://doi. org/10.1007/s00296-010-1547-6 PMid:20658240

Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NAC, Rosdiana I, Munir D. The role of tnf-α _induced mscs on suppressive inflammation by increasing tgf-β _and il-10. Open Access Maced J Med Sci. 2018;6(10):1779-83. https://doi.org/10.3889/oamjms.2018.404 PMid:30455748

Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, et al. The p110δ _isoform of the kinase PI(3) K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol. 2012;13(11):1045-54. https://doi.org/10.1038/ni.2426 PMid:23023391

Maynard CL, Weaver CT. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol Rev. 2008;226:219-23. https://doi.org/10.1111/j.1600-065X.2008.00711.x PMid:19161427

Godsell J, Rudloff I, Kandane-Rathnayake R, Hoi A, Nold MF, Morand EF, et al. Clinical associations of IL-10 and IL-37 in systemic lupus erythematosus. Sci Rep. 2016;6:1-10. https://doi.org/10.1038/srep34604

Grohmann U, Belladonna ML, Vacca C, Bianchi R, Fallarino F, Orabona C, et al. Positive regulatory role of IL-12 in macrophages and modulation by IFN-gamma. J Immunol. 2001;167(1):221-7. https://doi.org/10.4049/jimmunol.167.1.221 PMid:11418652

Muhar AM, Putra A, Warli SM, Munir D. Hypoxia-mesenchymal stem cells inhibit intra-peritoneal adhesions formation by upregulation of the IL-10 expression. Open Access Maced J Med Sci. 2019;7(23):3937-43. https://doi.org/10.3889/oamjms.2019.713 PMid:32165932

Ma X, Yan W, Zheng H, Du Q, Zhang L, Ban Y, et al. Regulation of IL-10 and IL-12 production and function in macrophages and dendritic cells. F1000Res. 2015;4:1. https://doi.org/10.12688/f1000research.7010.1 PMid:26918147

Rahim SS, Khan N, Boddupalli CS, Hasnain SE, Mukhopadhyay S. Interleukin-10 (IL-10) mediated suppression of IL-12 production in RAW 264.7 cells also involves c-rel transcription factor. Immunology. 2005;114(3):313-21. https://doi.org/10.1111/j.1365-2567.2005.02107.x PMid:15720433

Smith AM, Qualls JE, O’Brien K, Balouzian L, Johnson PF, Schultz-Cherry S, et al. A distal enhancer in Il12b is the target of transcriptional repression by the STAT3 pathway and requires the basic leucine zipper (B-ZIP) protein NFIL3. J Biol Chem. 2011;286(26):23582-90. https://doi.org/10.1074/jbc.m111.249235 PMid:21566115

Prochazkova J, Pokorna K, Holan V. IL-12 inhibits the TGF-β- dependent T cell developmental programs and skews the TGF-β- induced differentiation into a Th1-like direction. Immunobiology. 2012;217(1):74-82. https://doi.org/10.1016/j.imbio.2011.07.032 PMid:21903294

Darlan DM, Munir D, Jusuf NK, Ikhsan R, Alif I, Putra A. In vitro regulation of IL-6 and TGF-ß by mesenchymal stem cells in systemic lupus erythematosus patients. Med Glas (Zenica). 2020;17(2):448-53. PMid:32602296

Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med. 2005;201(7):1061- 7. https://doi.org/10.1084/jem.20042276 PMid:15809351

Wan YY, Flavell RA. ‘Yin-Yang’ functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunol Rev. 2007;220(1):199-213. https://doi.org/10.1111/j.1600-065x.2007.00565.x PMid:17979848