Siglec-G is a negative regulator of NF-kB activation and has pivotal roles in B-1 cell development and resistance to sepsis | Posted on:2009-01-20 | Degree:Ph.D | Type:Dissertation | University:The Ohio State University | Candidate:Ding, Cheng | Full Text:PDF | GTID:1444390005458618 | Subject:Biology | Abstract/Summary: | | The Siglecs (s&barbelow;ialic acid binding i&barbelow;mmunolg&barbelow;obulin-like Lectins) are I-type lectins 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-alpha 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-kappaB. By using IKK inhibitor to block the NF-kappaB 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-kappaB. Likewise, inhibition of NF-kappaB 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-kappaB activation and controls B-1a B cell expansion and host resistance to sepsis. | Keywords/Search Tags: | Siglec-g, Negative regulator, Cell, Activation, B-1a, Nf-kappab, Expansion | | Related items |
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