Belatacept Normalizes Specific Epigenetic-Cytokine Crosstalk in an Animal Model of Concanavalin A-Induced Acute Hepatic Injury

Doaa Khalid Ibrahim; Yassir Mustafa Kamal Al Mulla Hummadi; Huda Jaber Waheed

المؤلفون

Doaa Khalid Ibrahim Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq; Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq https://orcid.org/0000-0003-2001-7830
Yassir Mustafa Kamal Al Mulla Hummadi Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq https://orcid.org/0000-0002-7543-2807
Huda Jaber Waheed Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

الكلمات المفتاحية:

Belatacept، Interleukin-1β ، Liver injury ، MiRNA-155 ، MiRNA-223

الملخص

Background: Acute liver injury is still a major therapeutic problem. Studies have focused on the epigenetic environment that controls liver injury. MicroRNAs have become essential post-transcriptional regulators for the production of pro-inflammatory signaling cascades. Objective: This study evaluated the therapeutic potential of belatacept in hepatic injury by measurement of hepatic miRNA-155 and miRNA-223 and assessed its impact on IL-1β expression. Methods: Concanavalin-A was used to induce liver injury in Wistar rats, which were treated with prednisolone, belatacept, or a combination therapy. Hepatic expression of targeted miRNAs was quantified using RT-qPCR. Hepatic IL-1β was measured by the Western blotting technique. Results: The findings of this study identified that belatacept significantly normalized the expression of miRNA-155 and miRNA-223 (p<0.05). This epigenetic recovery was correlated with the stabilization of hepatic IL-1β level (p<0.01), Furthermore, belatacept demonstrated a therapeutic potency superior to prednisolone in mitigating liver injury, while combination therapy showed no significant synergistic advantage, suggesting a saturation of the common protective pathways. Conclusions: Belatacept ameliorates hepatic injury by targeting the miRNA-155/Akt/IL-1β pathway. Overall, miRNA-155 may offer a successful biomarker for treatment monitoring, and the miR-155/Akt pathway is a promising target for improving management of liver injury.

التنزيلات

بيانات التنزيل غير متوفرة بعد.

المراجع

Fadhil AF, Kamal YM, Waheed HJ. The hepatoprotective effect of Glycyrrhiza glabra roots extract against amiodarone-induced hepatotoxicity in male rats. Iraqi J Pharm Sci. 2024;33(2):190–196. doi: 10.31351/vol33iss2pp190-196

Hameed FG, Arif IS, Mohammed MM, Arif HS. Co-occurrence of Wilson disease and autoimmune hepatitis in a 14-year-old female: a case report. Al Mustansiriyah J Pharm Sci. 2021;21(2):1–8. doi: 10.32947/ajps.v21i2.803

Diener C, Keller A, Meese E. The miRNA–target interactions: an underestimated intricacy. Nucleic Acids Res. 2024;52(4):1544–1557. doi: 10.1093/nar/gkad1142.

Almajidi YQ, Muslim RK. Oligonucleotides as a novel therapeutic approach: an innovative area for drug delivery in neurological disorders. Al Mustansiriyah J Pharm Sci. 2025;25(1):143–169. doi: 10.32947/ajps.v25i1.1065.

Gehrke N, Hövelmeyer N, Waisman A, Straub BK, Weinmann-Menke J, Wörns MA, et al. Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1-driven autoinflammation. J Hepatol. 2018;68(5):986–995. doi: 10.1016/j.jhep.2018.01.008.

Diep S, Maddukuri M, Yamauchi S, Geshow G, Delk NA. Interleukin-1 and nuclear factor kappa B signaling promote breast cancer progression and treatment resistance. Cells. 2022;11(10):1673. doi: 10.3390/cells11101673.

Craig R, McIntosh K, Ho KH, McCulloch A, Riley C, Lawson C, et al. IL-1β stimulates a novel axis within the NF-κB pathway in endothelial cells regulated by IKKα and TAK-1. Biochem Pharmacol. 2025;232:116736. doi: 10.1016/j.bcp.2024.116736.

Mao H, Zhao X, Sun SC. NF-κB in inflammation and cancer. Cell Mol Immunol. 2025;22(8):811–839. doi: 10.1038/s41423-025-01310-w.

Cao YY, Wang Z, Wang ZH, Jiang XG, Lu WH. Inhibition of miR-155 alleviates sepsis-induced inflammation and intestinal barrier dysfunction by inactivating NF-κB signaling. Int Immunopharmacol. 2021;90:107218. doi: 10.1016/j.intimp.2020.107218.

Abdul-Aali TS, Altamemi IA, Muslim OT. Evaluation of miRNA-155 and miRNA-223 in blood in patients with ulcerative colitis. Int J Multidiscip Res Anal. 2023;6(10). doi: 10.47191/ijmra/v6-i10-49.

Han JM, Patterson SJ, Levings MK. The role of the PI3K signaling pathway in CD4+ T cell differentiation and function. Front Immunol. 2012;3:245. doi: 10.3389/fimmu.2012.00245.

Martinez-Usatorre A, Sempere LF, Carmona SJ, Carretero-Iglesia L, Monnot G, Speiser DE, et al. MicroRNA-155 expression is enhanced by T-cell receptor stimulation strength and correlates with improved tumor control in melanoma. Cancer Immunol Res. 2019;7(6):1013–1024. doi: 10.1158/2326-6066.CIR-18-0504.

Teteloshvili N, Smigielska-Czepiel K, Kroesen BJ, Brouwer E, Kluiver J, Boots AMH, et al. T-cell activation induces dynamic changes in miRNA expression patterns in CD4 and CD8 T-cell subsets. MicroRNA. 2015;4(2):117–122. doi: 10.2174/2211536604666150819194636.

Zuo WN, Zhu H, Li LP, Jin AY, Wang HQ. miR-155 promotes proliferation and inhibits apoptosis of nasopharyngeal carcinoma cells through targeting PTEN–PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2019;23(18):7935–7942. doi: 10.26355/eurrev_201909_19009.

Tabei Y, Nakajima Y. IL-1β-activated PI3K/AKT and MEK/ERK pathways coordinately promote induction of partial epithelial–mesenchymal transition. Cell Commun Signal. 2024;22(1):392. doi: 10.1186/s12964-024-01775-8.

Pang J, Huang P, Huang H, Ma J, He L, Lin X, et al. Molecular mechanism and role of miRNA-155 in podocyte apoptosis in lupus nephritis: SOCS1 protein expression regulates JAK/STAT pathway transduction. Int J Biol Macromol. 2025;304:140810. doi: 10.1016/j.ijbiomac.2025.140810.

Hu Y, Wu D, Feng X, Shi Z. Research on the effect of interfering with miRNA-155 on triple-negative breast cancer cells. Genes Genomics. 2022;44(9):1117-1124. doi: 10.1007/s13258-021-01106-y.