An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response.
Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator for nuclear receptors and other transcription factors. Although multiple physiological roles of SRC-3 have been revealed, its involvement in the inflammatory process remains unclear. Herein we show that SRC-3(-/-) mice are markedly hypersensitive to LPS-induced endotoxic shock. In response to LPS, SRC-3(-/-) macrophages produce significantly more proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta than wild-type controls, although they express similar amounts of cytokine mRNAs, suggesting that SRC-3 can exert effects at translational levels. Increased heavy polysome-associated TNF-alpha and IL-1beta mRNAs in SRC-3(-/-) macrophages implicate SRC-3 as a translational repressor. SRC-3 may cooperate with other translational repressors such as TIA-1 and TIAR to regulate cytokine mRNA translation. Collectively, our studies reveal an essential function of SRC-3 as a coordinator of inflammatory mRNA translation and as a physiologic protective factor against the lethal endotoxic shock triggered by an acute inflammatory response.
Yu
Chundong
C
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
York
Brian
B
Wang
Shu
S
Feng
Qin
Q
Xu
Jianming
J
O'Malley
Bert W
BW
D000818:Animals; D016207:Cytokines / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D056921:Nuclear Receptor Coactivator 3; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000473:pathology; D000074019:T-Cell Intracellular Antigen-1; D015534:Trans-Activators / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D000074019:T-Cell Intracellular Antigen-1; C499367:Tia1 protein, mouse; C489665:Tial1 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3