Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The severity of sepsis is associated with excessive inflammatory responses. MCP-1 induced protein (MCPIP1) could negatively regulate inflammatory responses by deubiquitinating K48 or K63 polyubiquitins of TNF receptor-associated factors. The function of MCPIP1 in negative regulation of inflammation is known, however, only the exact molecular pathway remains unknown. The aim of this study was to investigate whether and how MCPIP1 is involved in the regulation of lipopolysaccharides (LPS)-induced liver injury. Macrophages and a mouse model were induced by LPS treatment. Several in vitro assays, such as quantitative real-time PCR, immunoblotting, cell transfection, dual luciferase reporter assay, Enzyme-linked immunosorbent assay, and Hematoxylin-Eosin staining assay were used to explore the role of MCPIP1 and the interaction between MCPIP1, Sirtuin 1 (SIRT1), and microRNA-9 (miR-9). We found that the level of MCPIP1 increased and the level of SIRT1 decreased in LPS induced Kupffer cells or RAW 264.7 macrophages. Overexpression of MCPIP1 alleviated cytokine secretion and p65 nuclear translocation. Further study showed that MCPIP1 regulated p65 nuclear translocation by controlling p65 acetylation via promoting SIRT1 expression. Meanwhile, we found that miR-9 could directly regulate SIRT1 transcription by binding to the 3'-Untranslated Region of SIRT1 messenger RNA and that miR-9 was negatively regulated by MCPIP1. Importantly, overexpression of MCPIP1 in vivo could alleviate LPS-induced inflammation responses and liver injury in septic mice. These results demonstrated that MCPIP1 could alleviate inflammation responses and sepsis associated liver injury by promoting the expression of SIRT1, and miR-9 was involved in the MCPIP1-mediated regulation of SIRT1. Collectively, our results provide a possible novel signaling axis involving MCPIP1/miR-9/SIRT1 in LPS-induced septic mice.
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PMID:MCPIP1 alleviated lipopolysaccharide-induced liver injury by regulating SIRT1 via modulation of microRNA-9. 3109 43

Sepsis is a potentially fatal systemic inflammatory response syndrome caused by infection. In this study, we evaluated the effects of MCP-induced protein 1 (MCPIP1), a recently discovered inflammation-related ribonuclease, on sepsis-induced acute lung injury (ALI) and investigated the underlying mechanisms. Cecal ligation puncture and lipopolysaccharide induction were performed on Sprague-Dawley rats and RAW264.7 cells, respectively, to establish sepsis-induced ALI models. The proteasome inhibitor MG132 used as an activator of MCPIP1 overexpression, and we showed that MG132 can indeed increase the expression of MCPIP1. MCPIP1 overexpression induced by MG132 alleviated sepsis-induced pathologic changes, water content and protein leakage in the lungs, and induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. We also showed that MCPIP1 p showed romoted macrophage polarization from the M1 to the M2 type in sepsis-induced ALI. Furthermore, MCPIP1-enhanced M2 polarization was inhibited by an MCPIP1-targeting small interfering RNA (siMCPIP1) in RAW264.7 cells. Further mechanistic studies showed that the promotive effect of MCPIP1 on M2 polarization was related to the inhibition of c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Myc in the in vitro model. Conversely, siMCPIP1 transfection resulted in the recovery of JNK and c-Myc expression in LPS-treated cells. Taken together, these findings indicate that MCPIP1 plays a protective role in sepsis-induced ALI by modulating macrophage polarization through inhibition of the JNK/c-Myc signaling pathway. Our study presents a potentially novel therapeutic strategy for the treatment of lung injury involving the inflammatory cascade.
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PMID:MCP-induced protein 1 attenuates sepsis-induced acute lung injury by modulating macrophage polarization via the JNK/c-Myc pathway. 3132 31