PPAR-γ/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis
| Autor: | Stephanie L. Brandt, Fabiane Sônego, Ana Ferreira, Luciano Filgueiras, Carlos H. Serezani, Suojuan Wang, Fernando Q. Cunha, Flavia Sisti, Hong Du, Ana Paula Moreira Serezani, José C. Alves-Filho |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Immunology
Peroxisome proliferator-activated receptor Inflammation Pharmacology Biology Article Proinflammatory cytokine Sepsis Mice In vivo medicine MODELOS ANIMAIS DE DOENÇAS Immunology and Allergy Animals Hypoglycemic Agents Receptors Interleukin-10 Receptor chemistry.chemical_classification medicine.disease Interleukin-10 PPAR gamma Interleukin 10 Disease Models Animal STAT1 Transcription Factor chemistry Gene Expression Regulation Myeloid Differentiation Factor 88 Female Thiazolidinediones medicine.symptom Pioglitazone medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | Polymicrobial sepsis induces organ failure and is accompanied by overwhelming inflammatory response and impairment of microbial killing. Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear receptor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. The insulin-sensitizing drugs thiazolidinediones (TZDs) are specific PPAR-γ agonists. TZDs exert anti-inflammatory actions in different disease models, including polymicrobial sepsis. The TZD pioglitazone, which has been approved by the U.S. Food and Drug Administration, improves sepsis outcome; however, the molecular programs that mediate its effect have not been determined. In a murine model of sepsis, we now show that pioglitazone treatment improves microbial clearance and enhances neutrophil recruitment to the site of infection. We also observed reduced proinflammatory cytokine production and high IL-10 levels in pioglitazone-treated mice. These effects were associated with a decrease in STAT-1–dependent expression of MyD88 in vivo and in vitro. IL-10R blockage abolished PPAR-γ–mediated inhibition of MyD88 expression. These data demonstrate that the primary mechanism by which pioglitazone protects against polymicrobial sepsis is through the impairment of MyD88 responses. This appears to represent a novel regulatory program. In this regard, pioglitazone provides advantages as a therapeutic tool, because it improves different aspects of host defense during sepsis, ultimately enhancing survival. |
| Databáze: | OpenAIRE |
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