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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Foldenauer, Megan E. B. Berger, Elizabeth A. Hazlett, Linda D. McClellan, Sharon A. |
| Description | Country affiliation: United States Author Affiliation: Foldenauer ME ( Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.) |
| Abstract | IL-10 is important in the resistance response of BALB/c mice to experimental Pseudomonas aeruginosa corneal infection. However, the cellular mechanisms by which this anti-inflammatory cytokine is regulated remain unknown. Because the mammalian target of rapamycin (mTOR) regulates IL-10 in other disease models, the present study tested its role in bacterial keratitis. After infection, corneas of rapamycin versus control-treated BALB/c mice showed worsened disease, and real-time RT-PCR confirmed that mTOR mRNA levels were significantly decreased. Rapamycin treatment also increased clinical score, polymorphonuclear neutrophil (PMN) infiltration (determined by myeloperoxidase assay), and bacterial load, but it diminished PMN bactericidal activity. Inhibition of mTOR also led to elevated mRNA and protein levels of IL-12p40, matrix metalloproteinase 9, and inducible NO synthase, whereas mRNA and protein levels of IL-10, its regulator/effector STAT-3, and suppressor of cytokine signaling 3 (a proinflammatory cytokine regulator) were decreased. Furthermore, mTOR inhibition reduced levels of proapoptotic caspase-3 and increased levels of B cell lymphoma-2 (antiapoptotic), indicative of delayed apoptosis. mTOR inhibition also altered genes related to TLR signaling, including elevation of TLR4, TLR5, and IL-1R1, with decreases in IL-1R-associated kinase 1 and an inhibitor of NF-κB, NF-κB inhibitor-like 1. Rapamycin treatment also increased levels of IFN-γ and CCAAT/enhancer binding protein, ß, a gene that regulates expression of preprotachykinin-A (the precursor of substance P). Collectively, these data, as well as a rescue experiment using rIL-10 together with rapamycin, which decreased PMN in cornea, provide concrete evidence that mTOR regulates IL-10 in P. aeruginosa-induced bacterial keratitis and is critical to balancing pro- and anti-inflammatory events, resulting in better disease outcome. |
| ISSN | 00221767 |
| e-ISSN | 15506606 |
| DOI | 10.4049/jimmunol.1203094 |
| Journal | The Journal of Immunology |
| Issue Number | 11 |
| Volume Number | 190 |
| Language | English |
| Publisher | The American Association of Immunologists |
| Publisher Date | 2013-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Interleukin-10 Metabolism Keratitis Immunology Pseudomonas Infections Pseudomonas Aeruginosa Tor Serine-threonine Kinases Animals Apoptosis Drug Effects Genetics Bacterial Load Ccaat-enhancer-binding Protein-beta Cytokines Gene Expression Regulation Microbiology Pathology Mice Neutrophil Infiltration Neutrophils Nitrites Peroxidase Phagocytosis Rna, Messenger Stat3 Transcription Factor Sirolimus Pharmacology Antagonists & Inhibitors Toll-like Receptors Research Support, N.i.h., Extramural Discipline Immunology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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