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1.
J Dent Res ; 94(9): 1267-75, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26092379

ABSTRACT

Periodontitis (PD) is a chronic disease caused by the host inflammatory response to bacteria colonizing the oral cavity. In addition to tolerance to oral microbiome, a fine-tuned balance of IL-10 levels is critical to efficiently mount antimicrobial resistance without causing immunopathology. Clinical and animal studies support that adaptive T-helper (Th) cytokines are involved in the pathogenesis of alveolar bone destruction in PD. However, it remains unclear what type of Th response is related to human PD progression and what role IL-10 has on this process. We addressed the contribution of IL-10 in limiting Th1 and Th17 inflammatory response in murine and human PD. Through a combination of basic and translational approaches involving selected cytokine-deficient mice as well as human genetic epidemiology, our results demonstrate the requirement for IL-10 in fine-tuning the levels of Th17 (IL-17A and IL-17F) cytokines in experimental and human PD. Of novelty, we found that IL-17F correlated with protection in murine and human PD and was positively regulated by IL-10. To our knowledge, this is the first demonstration of the protective role for IL-17F in PD, its positive regulation by IL-10, and the potential differential role for IL-17A and IL-17F in periodontal disease.


Subject(s)
Cytokines/immunology , Interleukin-10/immunology , Periodontal Diseases/immunology , Th17 Cells/immunology , Animals , Enzyme-Linked Immunosorbent Assay , Humans , Interleukin-10/biosynthesis , Mice , Myeloid Differentiation Factor 88/physiology , Toll-Like Receptor 2/physiology
2.
Oncogene ; 32(28): 3350-8, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-22890319

ABSTRACT

Nucleophosmin (NPM), a ubiquitously and abundantly expressed protein, occurs in the nucleolus, shuttling between the nucleoplasm and cytoplasm. The NPM gene is mutated in almost 30% of human acute myeloid leukemia cells. NPM interacts with p53 and p19(Arf), directs localization of p19(Arf) in the nucleolus and protects the latter from degradation. Hepatocyte odd protein shuttling (HOPS) is also a ubiquitously expressed protein that moves between the nucleus and cytoplasm. Within the nucleus of resting cells, HOPS overexpression causes cell cycle arrest in G0/G1. HOPS knockdown causes centrosome hyperamplification leading to multinucleated cells and the formation of micronuclei. We demonstrate a direct interaction of HOPS with NPM and p19(Arf), resulting in a functionally active trimeric complex. NPM appeared to regulate HOPS half-life, which, in turn, stabilized p19(Arf) and controlled its localization in the nucleolus. These findings suggest that HOPS acts as a functional bridge in the interaction between NPM and p19(Arf), providing new mechanistic insight into how NPM and p19(Arf) will oppose tumor cell proliferation.


Subject(s)
Carrier Proteins/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Nuclear Proteins/metabolism , Animals , Carrier Proteins/chemistry , Carrier Proteins/genetics , Cell Cycle , Cell Line , Cyclin-Dependent Kinase Inhibitor p16/chemistry , Gene Knockout Techniques , Humans , Intracellular Signaling Peptides and Proteins , Membrane Proteins , Mice , Nuclear Proteins/chemistry , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Nucleophosmin , Protein Multimerization , Protein Stability , Protein Structure, Quaternary , Protein Transport
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