Xiaofan Li

FGF21 is a unique member of the fibroblast growth factors (FGFs) and a novel hormone that regulates glucose, lipid, and energy homeostasis. The beneficial effects of FGF21 reported thus far have mostly been from chronic treatments. In order to better understand the mechanism for FGF21 action, we evaluated the acute effects of FGF21 in vivo and in vitro. Here we report that a single injection of FGF21 acutely reduced plasma free fatty acid levels similar to its acute effects on plasma glucose in ob/ob mice. In vitro, FGF21 inhibited lipolysis in adipocytes during a short treatment and reduced total lipase activity. These results demonstrate the potential importance of adipocyte lipolysis to the observed acute improvements in plasma parameters.

We reported that both donor CD4(+) T and B cells in transplants were required for induction of an autoimmune-like chronic graft-versus-host disease (cGVHD) in a murine model of DBA/2 donor to BALB/c recipient, but mechanisms whereby donor B cells augment cGVHD pathogenesis remain unknown. In this study, we report that, although donor B cells have little impact on acute GVHD severity, they play an important role in augmenting the persistence of tissue damage in the acute and chronic GVHD overlapping target organs (i.e., skin and lung); they also markedly augment damage in a prototypical cGVHD target organ, the salivary gland. During cGVHD pathogenesis, donor B cells are activated by donor CD4(+) T cells to upregulate MHC II and costimulatory molecules. Acting as efficient APCs, donor B cells augment donor CD4(+) T clonal expansion, autoreactivity, IL-7Rα expression, and survival. These qualitative changes markedly augment donor CD4(+) T cells' capacity in mediating autoimmune-like cGVHD, so that they mediate disease in the absence of donor B cells in secondary recipients. Therefore, a major mechanism whereby donor B cells augment cGVHD is through augmenting the clonal expansion, differentiation, and survival of pathogenic CD4(+) T cells.

PAK4 is a member of the group B family of p21-activated kinases. Its expression is elevated in many cancer cell lines, and activated PAK4 is highly transforming, suggesting that it plays an important role in tumorigenesis. Although most previous work was carried out with overexpressed PAK4, here we used RNA interference to knock down endogenous PAK4 in cancer cells. By studying PAK4 knockdown HeLa cells, we demonstrated that endogenous PAK4 is required for anchorage-independent growth. Because cell survival is a key part of tumorigenesis and anchorage-independent growth, we studied whether PAK4 has a role in protecting cells from cell death. To address this, we studied the role for PAK4 downstream to the tumor necrosis factor (TNF) alpha receptor. Although overexpressed PAK4 was previously shown to abrogate proapoptotic pathways, here we demonstrate that endogenous PAK4 is required for the full activation of prosurvival pathways induced by TNFalpha. Our results indicate that PAK4 is required for optimal binding of the scaffold protein TRADD to the activated TNFalpha receptor through both kinase-dependent and kinase-independent mechanisms. Consequently, activation of several prosurvival pathways, including the NFkappaB and ERK pathways, is reduced in the absence of PAK4. Interestingly, constitutive activation of the NFkappaB and ERK pathways could compensate for the lack of PAK4, indicating that these pathways function downstream to PAK4. The role for PAK4 in regulating prosurvival pathways is a completely new function for this protein, and the connection between PAK4 and cell survival under stress helps explain its role in tumorigenesis and development.