Abstract
Unmethylated CpG oligodeoxynucleotides (CpG ODNs) activate immune cells to produce immune mediators. This study demonstrates that in murine macrophage RAW 264.7 cells, CpG ODN-mediated matrix metalloproteinase-9 (MMP-9) expression is regulated at transcriptional level and requires de novo protein synthesis. Inhibition of ERK and p38 MAPK, but not JNK, results in significant decrease of CpG ODN-induced MMP-9 expression. We found that endosomal maturation inhibitors, chloroquine and bafilomycin A, block CpG ODN-induced ERK and p38 MAPK activation and the subsequent MMP-9 expression. We also observed that CpG ODN induces NF-kappaB activation and NF-kappaB is a downstream target of p38 MAPK. Taken together, our data demonstrate that CpG ODN triggers MMP-9 expression via TLR-9 dependent ERK and p38 MAPK activation followed by NF-kappaB activation.
Highlights
Pathogen-derived structures activating the innate immune system include: cell wall products such as LPS and peptidoglycan, nucleic acids such as dsRNA, viral RNAs, and bacterial DNA (Janeway and Medzhitov, 2002)
We extended our previous observations of CpG ODN-induced Matrix metalloproteinase (MMP)-9 expression in murine macrophage RAW 264.7 cells
We further found that the CpG ODN elicits Toll-like receptor (TLR)-9 dependent ERK and p38 MAPK activation and the subsequent NF- B activation to produce matrix metalloproteinase-9 (MMP-9)
Summary
Pathogen-derived structures activating the innate immune system include: cell wall products such as LPS and peptidoglycan, nucleic acids such as dsRNA, viral RNAs, and bacterial DNA (Janeway and Medzhitov, 2002). Immunostimulatory activity of bacterial DNA depends on unmethylated CpG dinucleotides in particular base contexts (“CpG motif”) (Klinman et al, 1996; Krieg, 2002). CpG ODNs are recognized by a Toll-like receptor (TLR) 9 (Hemmi et al, 2000), which is expressed in the endoplasmic reticulum and transposes to DNAcontaining endosomes (Latz et al, 2004). Cellular recognition of bacterial DNA occurs after nonsequence-specific receptor-mediated uptake and endosomal acidification (Hacker et al, 1998, Macfarlane and Manzel, 1998). The nature of the receptor(s) mediating the uptake of exogenous DNA remains uncertain. Signal transduction pathways activated by TLRs induce the transcription of a series of cytokine/chemokine genes that are involved in the initiation or regulation of the inflammatory response. The recent progress in our understanding of TLR functions is accumulating that the signaling pathways associated with each TLR are not identical and may result in different biological responses
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