Proteasome-mediated regulation of CpG DNA- and peptidoglycan-induced cytokines, inflammatory genes, and mitogen-activated protein kinase activation.
Our previous work demonstrated that the proteasome is central to most of genes induced by lipopolysaccharide. In this study, we evaluated the role of the proteasome in response to two other microbial stimuli, CpG DNA (bacterial DNA) and peptidoglycan (PG), by measuring the effect of proteasome inhibition on cytokine secretion, induction of inflammatory gene expression, and activation of mitogen-activated protein kinases (MAPK) in murine macrophages. Pretreatment of macrophage cultures with lactacystin, a well-established proteasome inhibitor, significantly repressed tumor necrosis factor alpha secretion and tumor necrosis factor alpha and interleukin 1 beta gene expression, blocked the degradation of IkappaB, and dysregulated phosphorylation of MAPK induced by CpG DNA or PG. With respect to MAPK, lactacystin blocked expression of PG- or CpG-induced phosphorylated ERK1 and ERK2 and increased expression of phosphorylated c-Jun amino-terminal kinase but had no significant effect on phosphorylated p38. Increased expression of phoshorylated c-Jun amino-terminal kinase did not lead to an increase in AP-1 binding activity. Collectively, these data strongly support the conclusion that the proteasome is a key regulator of the CpG DNA- and PG-induced signaling pathways.
Shen
Jing
J
Department of Basic Medical Science, School of Medicine, and Shock/Trauma Research Center, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Gao
Jian Jun
JJ
Zhang
Guochi
G
Tan
Xiaoyu
X
Morrison
David C
DC
Papasian
Christopher
C
Vogel
Stefanie N
SN
Qureshi
Nilofer
N
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018899:CpG Islands; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004269:DNA, Bacterial / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010457:Peptidoglycan / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D004269:DNA, Bacterial; D010457:Peptidoglycan; D061988:Proteasome Inhibitors; D018808:Transcription Factor AP-1; C067713:lactacystin; D011505:Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine