Regulation of macrophage inflammatory function by AMP-activated protein kinase
AMP-aktive protein kinaz tarafından makrofaj inflamatuar işlevi yönetmeliği
- Tez No: 400001
- Danışmanlar: Belirtilmemiş.
- Tez Türü: Doktora
- Konular: Mikrobiyoloji, Microbiology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2009
- Dil: İngilizce
- Üniversite: University of Louisville
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 97
Özet
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Özet (Çeviri)
Metabolic and immune responses are the most basic and important survivalrequirements in multicellular organisms. Recent studies have shown a close link betweenmetabolism and inflammation. Identifying the molecular mechanisms linkingmetabolism and immunity is critical for the design of therapeutic treatments for metabolicand inflammatory diseases. AMP-activated protein kinase (AMPK) is an evolutionarilyconserved serine/threonine kinase that regulates energy homeostasis and metabolic stress.When the cellular AMP/ATP ratio is high, AMPK is activated, switching off ATPconsuminganabolic pathways and switching on ATP-producing catabolic pathways. Thegoal of this dissertation was to investigate the role of AMPK in macrophageinflammatory activity.Herein, we demonstrate a role of AMP-activated protein kinase (AMPK) as apotent counter-regulator of inflammatory signaling pathways in macrophages.Stimulation of macrophages with anti-inflammatory cytokines (i.e., IL-4, IL-10 andTGFß) resulted in the rapid phosphorylation/activation of AMPK, whereas stimulation ofmacrophages with a proinflammatory stimulus (LPS) resulted in AMPKdephosphorylation/inactivation. Inhibition of AMPK? expression by RNAinterferencedramatically increased the mRNA levels of LPS-induced TNF?, IL-6 andcyclooxygenase- 2 (COX-2). Likewise, expression of a dominant negative AMPK?1 inmacrophages enhanced TNF? and IL-6 protein synthesis in response to LPS stimulation,while diminishing the production of IL-10. In contrast, transfection of macrophages witha constitutively active form of AMPK?1 resulted in decreased LPS-induced TNF? andIL-6 production, and heightened production of IL-10. In addition, we found that AMPKnegatively regulated LPS-induced I?B-? degradation and positively regulated Aktactivation, possibly through PTEN inhibition, accompanied by inhibition of GSK3ß andactivation of CREB. Furthermore, we provided evidence that IL-10 activated AMPKthrough the LKB1 complex, an upstream kinase of AMPK. Overall, our resultsdemonstrate that AMPK directs signaling pathways in macrophages in a manner thatsuppresses proinflammatory responses and promotes macrophage polarization to an antiinflammatoryfunctional phenotype. Our work reveals AMPK as a molecular linkbetween metabolism and immunity. Therefore, AMPK may constitute a therapeutictarget for a broad range of metabolic and inflammatory diseases.
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