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osu1226876722.pdf (1.59 MB)
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Siglec-G Is A Negative Regulator Of Nf-Kb Activation And Has Pivotal Roles In B-1 Cell Development And Resistance To Sepsis
Author Info
Ding, Cheng
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1226876722
Abstract Details
Year and Degree
2008, Doctor of Philosophy, Ohio State University, Integrated Biomedical Sciences.
Abstract
The Siglecs (sialic acid binding immunolgobulin-like Lectins) are I-typelectins which bind to sialic acid bearing molecules and convey a wide array of information in the immune system. Siglec-G, the mouse homologue of human siglec-10, is a member of this family. Using a Siglec-G knock out, GFP knock-in model, we have found Siglec-G to be expressed on a variety of hematopoietic cells, with high levels on B cells and moderate levels on myeloid cells. Siglec-G deficient mice exhibit a dramatically expanded B-1a population in the peritoneal cavity. Blood IgM level is five folds higher in Siglec-G deficient mice. The enlarged peritoneal B-1a compartment results from post-natal expansion as the B- 1a precursor cells have higher frequencies in adult Siglec-G knock out mice bone marrow but not in fetal liver. Bone marrow chimera studies showed that Siglec-G deficient bone marrow cells have competitive advantage in reconstituting peripheral B cell populations in the peritoneal cavity, but not in the spleen. We have also found Siglec-G plays a key role in sepsis introduced by cecal ligation and puncture (CLP). Compared with wild type controls, Siglec-G-/- mice are more susceptible to CLP. Siglec-G-/- mice also showed more severe bacteremia and systemic damages, which led to accelerated deaths. Proinflammatory cytokines, especially TNF-α and IL-6 are significantly elevated in Siglec-G-/- mice post-CLP. Siglec-G-deficient peritoneal lavage cells contain more nuclear p65 and total phosphorylated p65 evidenced by western blot and ELISA, respectively. Gel shift assay also demonstrated higher accumulation of nuclear p50/p65. Therefore, Siglec-G works as a negative regulator of NF-κB. By using IKK inhibitor to block the NF-κB pathway, we blocked the expansion of peritoneal B- 1a cell at early stage postnatally. Thus, Siglec-G controls the expansion of peritoneal B-1a cells by repressing NF-κB. Likewise, inhibition of NF-κB activation resulted in dramatically reduced proinflammatory cytokine productions and significantly improved survival rate of Siglec-G mutant mice. Taken together, our data demonstrated that Siglec-G is a novel negative regulator for NF-κB activation and controls B-1a B cell expansion and host resistance to sepsis.
Committee
Thomas Boyd (Committee Chair)
Yang Liu (Committee Member)
Pan Zheng (Committee Member)
Xue-feng Bai (Committee Member)
Chack-Yung Yu (Committee Member)
Pages
135 p.
Subject Headings
Biomedical Research
Keywords
Siglec-G
;
B-1a
;
IgM
;
NF-kB
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Citations
Ding, C. (2008).
Siglec-G Is A Negative Regulator Of Nf-Kb Activation And Has Pivotal Roles In B-1 Cell Development And Resistance To Sepsis
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1226876722
APA Style (7th edition)
Ding, Cheng.
Siglec-G Is A Negative Regulator Of Nf-Kb Activation And Has Pivotal Roles In B-1 Cell Development And Resistance To Sepsis.
2008. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1226876722.
MLA Style (8th edition)
Ding, Cheng. "Siglec-G Is A Negative Regulator Of Nf-Kb Activation And Has Pivotal Roles In B-1 Cell Development And Resistance To Sepsis." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1226876722
Chicago Manual of Style (17th edition)
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Document number:
osu1226876722
Download Count:
951
Copyright Info
© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.