Interleukin 18 augments growth ability via NF-κB and p38/ATF2 pathways by targeting cyclin B1, cyclin B2, cyclin A2, and Bcl-2 in BRL-3A rat liver cells.
Interleukin 18 (IL-18) is a pleiotropic cytokine and capable of stimulating proliferation of certain cell types. Nonetheless, its effect on normal liver cells cultured remains unclear. In the present study, we discovered that IL-18 expression level was remarkably elevated at 3.3 and 8.6h after synchronized BRL-3A rat liver cells (G0 phase) re-entering the cell cycle. In addition, recombinant rat IL-18 (rrIL-18) at dosages 5-10 ng/ml increased the cell viability compared to untreated cells (with medium only) at 24 and 48 h (P<0.05). At the same time, the percentage of BrdU-labeling cells was also significantly increased (P<0.01). On the other hand, knockdown of IL-18 expression with short interference RNA (siRNA), the cell viability began to decline at 24h and significantly decreased compared to negative control (NC) at 48 and 72 h after transfection (P<0.05). Meanwhile, the number of cells in division phase (G2/M) was reduced in parallel. Further, after treatment with rrIL-18 (5 ng/ml), IL-18 and its receptor subunit IL-18Rα increased both at mRNA and protein levels. Moreover, the expression levels of adaptor molecule MyD88, transcription factor NF-κB and its downstream targets cyclin B1 and cyclin B2 were remarkably enhanced in BRL-3A cells stimulated by rrIL-18. Furthermore, transcription factor ATF2 and its targeted genes cyclin A2, Bcl-2 were also markedly increased after treatment with rrIL-18. These results demonstrated that IL-18 can augment cell proliferation via NF-κB and p38/ATF2 pathway by targeting cyclin B1, cyclin B2, cyclin A2 and Bcl-2 in BRL-3A rat liver cells.
College of Life Science, Henan Normal University, Xinxiang 453007, China; Key Laboratory for Cell Differentiation Regulation, Xinxiang 453007, China.
Jihong
J
Zhang
College of Life Science, Henan Normal University, Xinxiang 453007, China; Key Laboratory for Cell Differentiation Regulation, Xinxiang 453007, China.
Cuiyun
C
Pan
College of Life Science, Henan Normal University, Xinxiang 453007, China; Key Laboratory for Cell Differentiation Regulation, Xinxiang 453007, China.
Tiantian
T
Xu
College of Life Science, Henan Normal University, Xinxiang 453007, China; Key Laboratory for Cell Differentiation Regulation, Xinxiang 453007, China.
Zhipeng
Z
Niu
College of Life Science, Henan Normal University, Xinxiang 453007, China; Key Laboratory for Cell Differentiation Regulation, Xinxiang 453007, China.
Chengkai
C
Ma
College of Life Science, Henan Normal University, Xinxiang 453007, China; Key Laboratory for Cell Differentiation Regulation, Xinxiang 453007, China. Electronic address: cellkeylab@126.com.
Cunshuan
C
Xu
D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D056765:Cyclin B2 / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; C503722:Ccna2 protein, rat; C534701:Ccnb1 protein, rat; C503761:Ccnb2 protein, rat; C530106:Ccnd1 protein, rat; D056751:Cyclin A2; D056744:Cyclin B1; D056765:Cyclin B2; D020382:Interleukin-18; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins; D019938:Cyclin D1; D048051:p38 Mitogen-Activated Protein Kinases
Cell proliferation; Interleukin 18; Liver cells; Signaling pathway; Transcription factor