Biomedical subjects

B Ken Choi

Publications and source records attributed to B Ken Choi.

3 recordsLinked to original sources

PubMed2004

C-terminal SRC kinase controls acute inflammation and granulocyte adhesion.

To establish whether the widely expressed regulator of Src family kinases Csk contributes to the control of acute inflammation in vivo, we inactivated csk in granulocytes by conditional mutagenesis (Cre/loxP). Mutant mice (Csk-GEcre) developed acute multifocal inflammation in skin and lung. Animals were protected from the disease in a microbiologically controlled environment, but remained hypersensitive to LPS-induced shock. Csk-deficient granulocytes showed enhanced spontaneous and ligand-induced degranulation with hyperinduction of integrins. This hyperresponsiveness was associated with hyperadhesion and impaired migratory responses in vitro. Hyperphosphorylation of key signaling proteins such as Syk and Paxillin in mutant granulocytes further supported breakdown of the activation threshold set by Csk. By enforcing the need for ligand engagement Csk thus prevents premature granulocyte recruitment while supporting the motility of stimulated cells through negative regulation of cell adhesion.

Acute Disease↗

PubMed2003

Redirection of B cell responsiveness by transforming growth factor beta receptor.

The multifunctional transforming growth factor beta receptor (TbetaR) ligand pair plays a central role in the regulation of lymphocyte homeostasis and prevention of autoimmunity. Although the mechanisms underlying the induction of transcriptional modulators by TbetaR have been studied in considerable detail, relatively little is known about the regulatory pathways targeted. To shed light on the mechanisms involved in negative regulation of B cell responses we identified TbetaR-dependent transcriptome changes by comparative gene expression profiling of normal and TbetaR-deficient primary B cells. The data reveal TbetaR-mediated induction of inhibitors of antigen receptor signaling (Ship-1, CD72) as well as inhibitors of the Jak/Stat pathway and signaling by means of Toll-like receptors (SOCS1,3). These inhibitory effects are complemented by induction of antiproliferative transcription factors. In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca2+ flux (inositol trisphosphate receptor subtype 2) are induced by TbetaR, indicating enhancement of the Ca2+ storage/ release system and chemotactic responses. Suppression of proapoptotic genes suggests support of cell survival. Confirming the shift in B cell responsiveness, antigen-receptor-mediated activation of Syk and phospholipase C-gamma2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2+ release, and cell survival are enhanced in transforming growth factor-beta-sensitive B cells. The data provide a molecular basis for TbetaR-mediated inhibition of B cell responsiveness and indicate that TbetaR maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to microenvironmental cues.

Animals↗

PubMed2003

Granulocyte function in grancalcin-deficient mice.

Grancalcin, one of the penta-EF-hand Ca(2+) binding proteins, is expressed at high levels in polymorphonuclear granulocytes (neutrophils). EF-hand proteins are implicated in the regulation of diverse processes including cell migration, apoptosis, and mobilization of neutrophil effector functions. To determine the role of grancalcin in vivo, we inactivated the gene encoding grancalcin (Gca) in embryonic stem cells and generated grancalcin-deficient mice. Homozygous Gca mutants appeared healthy and reproduced normally. Leukocyte recruitment into the peritoneal cavity upon induction of inflammation was not significantly affected by the absence of grancalcin. The mutants also resisted systemic fungal infection similarly to wild-type mice, and in vitro killing of Staphylococcus aureus by inflammatory cells was not significantly impaired. While marginally increased survival rates of mutants faced with endotoxic shock may indicate a contribution of grancalcin to immunopathogenesis, it is not essential for vital leukocyte effector functions required to control microbial infections.

Animals↗