Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA

Speaker: 陳銘祥                            Time: 11/10/2004, 14: 00~ 15: 00

Commentator: 邵長平 博士                   Place: Room 601

Abstract:

     The intestinal epithelial cells constitute the first line defending against pathogens by both mechanical barrier and production of proinflammatory cytokines that initiate the host immune response. However, the abundant commensal bacteria can colonize in human gastrointestinal tract without causing uncontrolled inflammatory storm by as yet unclear mechanisms. In this study, the authors discovered that Bacteroides thetaiotaomicron, the chief microflora in human gastrointestinal tract, can attenuate inflammation induced by Salmonella enterica serovar Enteritidis (S. enteritidis). First, B. thetaiotaomicron selectively reduced the expression of proinflammtory cytokines, such as IL-8, that were induced in the presence of S. enteritidis. By immunofluo- rescence analysis and electrophoresis mobility shift assay, they found that the nuclear transcription factor NF-κB, which could activate the expression of proinflammatory cytokines, was also inhibited by export of NF-κB subunit RelA from the nucleus (1). This inhibition was independent of nuclear export receptor, Crm-1. Second, the peroxisome-proliferator activated receptor-γ (PPAR-γ) as one modulator of inflamma- tion (2) was shown to have similar patterns of cellular localization as that of RelA after coculture of S. enteritidis and B. thetaiotaomicron. In vitro translation experiment demonstrated the binding between RelA and PPAR-γ. Finally, introduction of dominant negative PPAR-γ or RNAi transfection showed that the export of RelA induced by B. thetaiotaomicron was blocked by reduction of functional PPAR-γ in nucleus. Meanwhile, anti-inflammatory effects were also abolished. Therefore, the PPAR-γ- dependent nuclear export of RelA activated by commensal microflora appears to be a unique anti-inflammatory mechanism and may serve as a therapeutic cellular target for uncontrolled inflammation.

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2.      Ricote, C. F., May, M. J. & Kopp, E. B.. The peroxisome proliferator-activated receptor γ (PPAR-γ) as a regulator of monocyte/macrophage function. J. Leukoc. Biol. 66, 733-739 (1999).

3.      Denise K., et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nat. Immunol. 5, 104 - 112 (2004).