In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Choudhury, Barun K.; Wild, James S.; Alam, Rafeul; Klinman, Dennis M.; Boldogh, István; Dharajiya, Nilesh; Mileski, William J.; Sur, Sanjiv

doi:10.4049/jimmunol.169.10.5955

Cited by 42 publications

(37 citation statements)

References 37 publications

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“…This hypothesis is supported by our observation that even though the persons with emphysema have abstained from smoking for months, their pulmonary p-ERK activity is significantly higher than that of active smokers without the disease. In addition, these data demonstrate that cigarette smoke activates MMP-1 in the absence of a complete inflammatory program, as shown by our epithelial culture system, providing further support for chronic obstructive pulmonary disease research efforts targeted at not only proteolytic enzymes, but also the internal signaling pathways of cells of the lung (47,48).…”

Section: Discussionsupporting

confidence: 73%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

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Section: Discussionsupporting

confidence: 73%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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“…p38 MAPK has been reported to be involved in IL-12 production (21, 38). Recent reports have also revealed that SB202190, a p38 MAPK inhibitor, inhibits CpG oligodeoxynucleotide-induced IL-12 production in macrophages (39). However, the p38 MAPK inhibitors did not affect the p43-induced NF-B DNA-binding activity (data now shown), suggesting that p43 induced IL-12 production in macrophages via two independent pathways, the NF-B and PKC/p38 MAPK pathways.…”

Section: Discussionmentioning

confidence: 76%

The Novel Cytokine p43 Induces IL-12 Production in Macrophages via NF-κB Activation, Leading to Enhanced IFN-γ Production in CD4+ T Cells

Kim

Kim²,

Kim

et al. 2006

The Journal of Immunology

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Recently, we determined that p43, an auxiliary factor of mammalian multiaminoacyl-tRNA synthetases, is secreted, and functions as a novel pleiotropic cytokine. In this study, we have attempted to characterize the effects of p43 on the generation of IL-12 in mouse macrophages. p43 was determined to induce significant IL-12 production from mouse macrophages in a dose-dependent manner. The stimulatory effect of p43 on the activation of IL-12p40 promoter was mapped to a region harboring an NF-κB binding site. The nuclear extracts from the p43-stimulated macrophages exhibited profound NF-κB DNA-binding activity, as determined by the EMSA. In addition, the p43-stimulated IL-12 induction and NF-κB DNA-binding activity were significantly suppressed by caffeic acid phenethyl ester and BAY11-7082, both inhibitors of NF-κB activation, indicating that p43 induced the production of IL-12 in macrophages mainly via the activation of NF-κB. Importantly, p43 increased the level of IFN-γ production in the Ag-primed lymph node cells, but had no effect on IL-4 levels. The addition of a neutralizing anti-IL-12p40 mAb to the cell cultures resulted in a decrease of the production of p43-enhanced IFN-γ by the keyhole limpet hemocyanin-primed lymph node cells. Furthermore, coincubation with p43-pretreated macrophages enhanced the production of IFN-γ by the keyhole limpet hemocyanin-primed CD4+ T cells, thereby indicating that p43 may enhance IFN-γ expression in CD4+ T cells via the induction of IL-12 production in macrophages. These results indicate that p43 may play an essential role in the development of the Th1 immune responses associated with cancer immunotherapy and protective immunity against intracellular pathogens.

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“…Activation of TLR9 by CpG oligos triggers stress kinase (28,29) and NF-B (30) signaling pathways, leading to the activation of multiple transcription factors, which in turn up-regulate cytokine secretion and expression of cell surface markers. In the present study, treatment of J774 cells with RpG oligos and immunomers led to the activation of NF-B and phosphorylation of p38 in J774 cells, as occurred also with CpG oligos, suggesting that similar signaling pathways were involved in both cases (Fig.…”

Section: Discussionmentioning

confidence: 99%

A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif

Kandimalla

Bhagat

Zhu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial and synthetic DNAs containing CpG dinucleotides in specific sequence contexts activate the vertebrate immune system through Toll-like receptor 9 (TLR9). In the present study, we used a synthetic nucleoside with a bicyclic heterobase [1-(2 -deoxy-␤-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine; R] to replace the C in CpG, resulting in an RpG dinucleotide. The RpG dinucleotide was incorporated in mouse-and human-specific motifs in oligodeoxynucleotides (oligos) and 3 -3-linked oligos, referred to as immunomers. Oligos containing the RpG motif induced cytokine secretion in mouse spleen-cell cultures. Immunomers containing RpG dinucleotides showed activity in transfected-HEK293 cells stably expressing mouse TLR9, suggesting direct involvement of TLR9 in the recognition of RpG motif. In J774 macrophages, RpG motifs activated NF-B and mitogen-activated protein kinase pathways. Immunomers containing the RpG dinucleotide induced high levels of IL-12 and IFN-␥, but lower IL-6 in time-and concentrationdependent fashion in mouse spleen-cell cultures costimulated with IL-2. Importantly, immunomers containing GTRGTT and GARGTT motifs were recognized to a similar extent by both mouse and human immune systems. Additionally, both mouse-and humanspecific RpG immunomers potently stimulated proliferation of peripheral blood mononuclear cells obtained from diverse vertebrate species, including monkey, pig, horse, sheep, goat, rat, and chicken. An immunomer containing GTRGTT motif prevented conalbumin-induced and ragweed allergen-induced allergic inflammation in mice. We show that a synthetic bicyclic nucleotide is recognized in the C position of a CpG dinucleotide by immune cells from diverse vertebrate species without bias for flanking sequences, suggesting a divergent nucleotide motif recognition pattern of TLR9.T he immune system of vertebrates recognizes synthetic oligodeoxynucleotides, bacterial and plasmid DNAs containing unmethylated CpG dinucleotides in specific sequence contexts (CpG motifs) (1-5). This recognition is mediated by a molecular pattern recognition receptor, Toll-like receptor 9 (TLR9) (6). Upon activation by CpG DNA, TLR9 initiates signaling pathways that activate several transcription factors, including NF-B and AP-1 (3-5). The immunological events that occur after CpG DNA activation of the immune system include B cell proliferation, increased expression of MHC class II antigens, increased synthesis of RNA and DNA, and the release of a number of cytokines and chemokines (7-9). The potent T helper 1 immune response produced by CpG activation of the innate immune system supports the broad therapeutic application of CpG DNA against cancer, infectious diseases, asthma, and allergies and as adjuvants in immunotherapy. Several studies have demonstrated the potential effectiveness of CpG DNAs as therapies in animal models, and a number of CpG DNAs are currently being tested in clinical trials (4, 10).We previously showed that two CpG DNAs attached through their 5Ј ends failed to stimulate the immune syst...

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In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Cited by 42 publications

References 37 publications

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

The Novel Cytokine p43 Induces IL-12 Production in Macrophages via NF-κB Activation, Leading to Enhanced IFN-γ Production in CD4+ T Cells

A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif

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