Abstract:
:Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1). Studies with macrophages lacking ERR alpha demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-gamma. As a result, mice lacking ERR alpha are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-gamma-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor gamma coactivator-1 beta), which appears to be a direct target for the IFN-gamma/STAT-1 signaling cascade. Thus, ERR alpha and PGC-1 beta act together as a key effector of IFN-gamma-induced mitochondrial ROS production and host defense.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Sonoda J,Laganière J,Mehl IR,Barish GD,Chong LW,Li X,Scheffler IE,Mock DC,Bataille AR,Robert F,Lee CH,Giguère V,Evans RMdoi
10.1101/gad.1553007subject
Has Abstractpub_date
2007-08-01 00:00:00pages
1909-20issue
15eissn
0890-9369issn
1549-5477pii
21/15/1909journal_volume
21pub_type
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