Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome.
The purpose of our study was to understand if Toll-like receptor 9 (TLR9) activation could contribute to the control of inflammation in Sjogren's syndrome. To this end, we manipulated TLR9 signaling in non-obese diabetic (NOD) and TLR9(-/-) mice using agonistic CpG oligonucleotide aptamers, TLR...
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2011
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oai:doaj.org-article:738cb2a18b1149fca36a75e04b8ee92c2021-11-18T07:32:36ZActivation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome.1932-620310.1371/journal.pone.0028727https://doaj.org/article/738cb2a18b1149fca36a75e04b8ee92c2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22174879/?tool=EBIhttps://doaj.org/toc/1932-6203The purpose of our study was to understand if Toll-like receptor 9 (TLR9) activation could contribute to the control of inflammation in Sjogren's syndrome. To this end, we manipulated TLR9 signaling in non-obese diabetic (NOD) and TLR9(-/-) mice using agonistic CpG oligonucleotide aptamers, TLR9 inhibitors, and the in-house oligonucleotide BL-7040. We then measured salivation, inflammatory response markers, and expression of proteins downstream to NF-κB activation pathways. Finally, we labeled proteins of interest in salivary gland biopsies from Sjogren's syndrome patients, compared to Sicca syndrome controls. We show that in NOD mice BL-7040 activates TLR9 to induce an alternative NF-κB activation mode resulting in increased salivation, elevated anti-inflammatory response in salivary glands, and reduced peripheral AChE activity. These effects were more prominent and also suppressible by TLR9 inhibitors in NOD mice, but TLR9(-/-) mice were resistant to the salivation-promoting effects of CpG oligonucleotides and BL-7040. Last, salivary glands from Sjogren's disease patients showed increased inflammatory and decreased anti-inflammatory biomarkers, in addition to decreased levels of alternative NF-κB pathway proteins. In summary, we have demonstrated that activation of TLR9 by BL-7040 leads to non-canonical activation of NF-κB, promoting salivary functioning and down-regulating inflammation. We propose that BL-7040 could be beneficial in treating Sjogren's syndrome and may be applicable to additional autoimmune syndromes.Adi Gilboa-GeffenYochai WolfGeula HaninNaomi Melamed-BookMarjorie PickEstelle R BennettDavid S GreenbergSusan LesterMaureen RischmuellerHermona SoreqPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 12, p e28727 (2011) |
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Medicine R Science Q Adi Gilboa-Geffen Yochai Wolf Geula Hanin Naomi Melamed-Book Marjorie Pick Estelle R Bennett David S Greenberg Susan Lester Maureen Rischmueller Hermona Soreq Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. |
| description |
The purpose of our study was to understand if Toll-like receptor 9 (TLR9) activation could contribute to the control of inflammation in Sjogren's syndrome. To this end, we manipulated TLR9 signaling in non-obese diabetic (NOD) and TLR9(-/-) mice using agonistic CpG oligonucleotide aptamers, TLR9 inhibitors, and the in-house oligonucleotide BL-7040. We then measured salivation, inflammatory response markers, and expression of proteins downstream to NF-κB activation pathways. Finally, we labeled proteins of interest in salivary gland biopsies from Sjogren's syndrome patients, compared to Sicca syndrome controls. We show that in NOD mice BL-7040 activates TLR9 to induce an alternative NF-κB activation mode resulting in increased salivation, elevated anti-inflammatory response in salivary glands, and reduced peripheral AChE activity. These effects were more prominent and also suppressible by TLR9 inhibitors in NOD mice, but TLR9(-/-) mice were resistant to the salivation-promoting effects of CpG oligonucleotides and BL-7040. Last, salivary glands from Sjogren's disease patients showed increased inflammatory and decreased anti-inflammatory biomarkers, in addition to decreased levels of alternative NF-κB pathway proteins. In summary, we have demonstrated that activation of TLR9 by BL-7040 leads to non-canonical activation of NF-κB, promoting salivary functioning and down-regulating inflammation. We propose that BL-7040 could be beneficial in treating Sjogren's syndrome and may be applicable to additional autoimmune syndromes. |
| format |
article |
| author |
Adi Gilboa-Geffen Yochai Wolf Geula Hanin Naomi Melamed-Book Marjorie Pick Estelle R Bennett David S Greenberg Susan Lester Maureen Rischmueller Hermona Soreq |
| author_facet |
Adi Gilboa-Geffen Yochai Wolf Geula Hanin Naomi Melamed-Book Marjorie Pick Estelle R Bennett David S Greenberg Susan Lester Maureen Rischmueller Hermona Soreq |
| author_sort |
Adi Gilboa-Geffen |
| title |
Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. |
| title_short |
Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. |
| title_full |
Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. |
| title_fullStr |
Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. |
| title_full_unstemmed |
Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome. |
| title_sort |
activation of the alternative nfκb pathway improves disease symptoms in a model of sjogren's syndrome. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/738cb2a18b1149fca36a75e04b8ee92c |
| work_keys_str_mv |
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