Journal
ENDOCRINOLOGY
Volume 157, Issue 11, Pages 4121-4132Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2016-1060
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Funding
- National Natural Science Foundation of China Grants [81400677, 81270548, 81370016]
- Science and Technology Project of Shaanxi Grants [2014KW20-03, 2016KW-023]
- Fundamental Research Funds for the Central Universities Grant [08143014]
- Higher Specialized Research Fund for the Doctoral Program of the New Class of Teachers Funded Project [20130201120081]
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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-alpha, inducing macrophage proliferation. Furthermore, the increased number, proapoptotic proteins, and nuclear factor-kappa b (NF-kappa B) phosphorylation status of the infiltrating macrophages were accompanied by increased TNF-alpha 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-alpha 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-alpha/nuclear factor-kappa b pathway. This potentially represents a promising therapeutic target in improving islet graft survival.
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