ABSTRACT
Since bacterial invasion into host cells is a critical step in the infection process and the predominance of multiple-antibiotic-resistant Klebsiella (K.) pneumoniae strains, using molecular agents to interfere with K. pneumoniae invasion is an attractive approach for the prevention of infection and suppress the immune inflammatory response. In previous studies by our group, high-mobility group nucleosome-binding domain 2 (HMGN2) protein was shown to exhibit anti-bacterial activity in vitro. The objective of the present study was to investigate the effects of HMGN2 protein on the invasion of K. pneumoniae 03183 in vivo. The results showed that pre-treatment with 128 µg/ml HMGN2 significantly reduced K. pneumoniae 03183 invasion into mouse lungs and increased the mRNA expression of CXCL1 and LCN2 within 2 h. Immunohistochemical staining showed that F-actin expression was significantly decreased, and fluorescence microscopy and western blot analysis further demonstrated that HMGN2 significantly blocked K. pneumoniae 03183-induced actin polymerization. These changes implied that HMGN2 may provide protection against K. pneumoniae 03183 infection in vivo.
Subject(s)
Anti-Bacterial Agents/pharmacology , HMGN2 Protein/pharmacology , Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Lung/drug effects , Pneumonia, Bacterial/drug therapy , Actins/genetics , Actins/immunology , Acute-Phase Proteins/agonists , Acute-Phase Proteins/genetics , Acute-Phase Proteins/immunology , Animals , Anti-Bacterial Agents/biosynthesis , Chemokine CXCL1/agonists , Chemokine CXCL1/genetics , Chemokine CXCL1/immunology , Female , Gene Expression , HMGN2 Protein/biosynthesis , Host-Pathogen Interactions/drug effects , Humans , Klebsiella Infections/immunology , Klebsiella Infections/microbiology , Klebsiella Infections/pathology , Klebsiella pneumoniae/physiology , Lipocalin-2 , Lipocalins/agonists , Lipocalins/genetics , Lipocalins/immunology , Lung/microbiology , Mice , Mice, Inbred C57BL , Oncogene Proteins/agonists , Oncogene Proteins/genetics , Oncogene Proteins/immunology , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/microbiology , Pneumonia, Bacterial/pathology , RNA, Messenger/genetics , RNA, Messenger/immunology , Recombinant Proteins/biosynthesis , Recombinant Proteins/pharmacologyABSTRACT
The steroid receptor coactivator 1 (SRC1) regulates key metabolic pathways, including glucose homeostasis. SRC1(-/-) mice have decreased hepatic expression of gluconeogenic enzymes and a reduction in the rate of endogenous glucose production (EGP). We sought to determine whether decreasing hepatic and adipose SRC1 expression in normal adult rats would alter glucose homeostasis and insulin action. Regular chow-fed and high-fat-fed male Sprage-Dawley rats were treated with an antisense oligonucleotide (ASO) against SRC1 or a control ASO for 4 wk, followed by metabolic assessments. SRC1 ASO did not alter basal EGP or expression of gluconeogenic enzymes. Instead, SRC1 ASO increased insulin-stimulated whole body glucose disposal by ~30%, which was attributable largely to an increase in insulin-stimulated muscle glucose uptake. This was associated with an approximately sevenfold increase in adipose expression of lipocalin-type prostaglandin D2 synthase, a previously reported regulator of insulin sensitivity, and an approximately 70% increase in plasma PGD2 concentration. Muscle insulin signaling, AMPK activation, and tissue perfusion were unchanged. Although GLUT4 content was unchanged, SRC1 ASO increased the cleavage of tether-containing UBX domain for GLUT4, a regulator of GLUT4 translocation. These studies point to a novel role of adipose SRC1 as a regulator of insulin-stimulated muscle glucose uptake.
