title: Inactivation of p27kip1Promoted Nonspecific Inflammation by Enhancing Macrophage Proliferation in Islet Transplantation.
abstract: Islet transplantation suffers from low efficiency caused by nonspecific inflammation-induced graft loss after transplantation. This study reports increased islet loss and enhanced inflammatory response in p27-deficient mice (p27-/-) and proposes a possible mechanism. Compared with wild type, p27-/- mice showed more severe functional injury of islet, with increased serum levels of inflammatory cytokines IL-1 and TNF-α, inducing macrophage proliferation. Furthermore, the increased number, proapoptotic proteins, and nuclear factor-kappa b (NF-κB) phosphorylation status of the infiltrating macrophages were accompanied by increased TNF-α mRNA level of islet graft site in p27-/- mice. Moreover, in vitro, we found that macrophages were still activated and cocultured with islet and promoted islet loss even blocking the direct effect of TNF-α on islets. Malondialdehyde (MDA, an end product of lipid peroxidation) in islet and media were increased after cocultured with macrophages. p27 deficiency also increased macrophage proliferation and islet injury. Therefore, p27 inactivation promotes injury islet graft loss via the elevation of proliferation and inflammatory cytokines secretion in infiltrating macrophages which induced nonspecific inflammation independent of TNF-α/nuclear factor-kappa b pathway. This potentially represents a promising therapeutic target in improving islet graft survival.
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Xinshun
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Puxun
authors.initials: P
authors.lastname: Tian
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Renal Transplantation (Y.L., X.D., X.T., X.F., J.Z., P.T., C.D., W.X.), Center of Nephrology, the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; Institute of Organ Transplantation (Y.L., X.D., X.T, X.F., J.Z., P.T., C.D., W.X.), Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China; and Departments of Rheumatism and Immunology (P.F.) and Hepatobiliary (J.G.), the First Affiliated Hospital Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, 710061, People's Republic of China.
authors.forename: Wujun
authors.initials: W
authors.lastname: Xue
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007375:Interleukin-1 / Q000097:blood; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D007375:Interleukin-1; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27