Knockdown of MicroRNA-155 in Kupffer Cells Results in Immunosuppressive Effects and Prolongs Survival of Mouse Liver Allografts

Li, Jinzheng; Gong, Junhua; Li, Peizhi; Li, Min; Liu, Yiming; Liang, Shaoyong; Gong, Jianping

doi: 10.1097/TP.0000000000000061
Basic and Experimental Research

Background: Our previous studies have shown that Kupffer cells (KCs) play a crucial role in postoperative pathologic changes. Recent reports have demonstrated that microRNA-155 (miR-155) is associated with inflammation and upregulation of proinflammatory mediators in the peripheral blood and allografts of transplant patients. However, the precise mechanism for this remains unknown.

Methods: KCs isolated from BALB/c mice were transfected with miR-155 mimic or inhibitor. Levels of suppressor of cytokine signaling 1/Janus kinase/signal transducer and activator of transcription (SOCS1/JAK/STAT) proteins and surface molecules (MHC-II, CD40, and CD86) were then measured. T-cell proliferation and apoptosis were evaluated in mixed lymphocyte reactions. Orthotopic liver transplantation was performed in mice after miR-155 short hairpin RNA lentivirus treatment, and postoperative survival, liver function and histology, and mRNA and protein expression were analyzed.

Results: miR-155 knockdown in KCs decreased MHC-II, CD40, and CD86 expression, suppressed antigen-presenting function, and affected SOCS1/JAK/STAT inflammatory pathways. In addition, KCs transfected with miR-155 inhibitor and cocultured with T lymphocytes showed reduced T-cell responses but a greater number of apoptotic T cells. Finally, miR-155 suppression in graft liver prolonged liver allograft survival and improved liver function. The changes were closely associated with the levels of T helper 1 and 2 (Th1/Th2) cytokines and T-cell apoptosis, but a direct mechanistic link in vivo was not established.

Conclusion: These data suggest miR-155 regulates the balance of Th1/Th2 cytokines and the maturation and function of KCs in mice. miR-155 repression in KCs positively regulates KC function toward immunosuppression and prolongs liver allograft survival.

Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

This project was supported by the National Natural Science Foundation of China (No. 81070374, 81200329).

The authors declare no conflicts of interest.

Address correspondence to: Shaoyong Liang, Ph.D., and Jianping Gong, Ph.D., Department of Hepatobiliary Surgery, Secondary Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.

E-mail: liangshaoyong_cqmu@126.com; gongjianping11@126.com

J.L. and J.G. contributed equally to this article.

J.L. and J.G. participated in performing the studies and writing the article. P.L. and Y.L. participated in performing the research. M.L. and S.L. participated in analyzing the data. S.L. and J.G. participated in performing the studies and editing the final draft of the article.

Received 10 July 2013. Revision requested 30 July 2013.

Accepted 19 December 2013.

Accepted February 14, 2014

© 2014 by Lippincott Williams & Wilkins