Multiple sclerosis (MS) is a chronic neurological disease of unknown etiology, but a genetic basis for the disease is undisputed. We have reported that CD24 is required for the pathogenicity of autoreactive T cells in experimental autoimmune encephalomyelitis, the mouse model of MS. Here we investigate the contribution of CD24 to MS by studying single-nucleotide polymorphism in the ORF among 242 MS patients and 207 population controls. This single-nucleotide polymorphism results in replacement of alanine (CD24 a ) with valine (CD24 v ) in the mature protein. We found that the CD24 v/v renders a >2-fold increase in the relative risk of MS in the general population (P ‫؍‬ 0.023). Among familial MS, the CD24 v allele is preferentially transmitted into affected individuals (P ‫؍‬ 0.017). Furthermore, 50% of CD24 v/v patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24 a/v (P ‫؍‬ 0.00037) and CD24 a/a (P ‫؍‬ 0.0016) patients did so in 16 and 13 years, respectively. Moreover, our data suggest that the CD24 v/v patients expressed higher levels of CD24 on peripheral blood T cells than did the CD24 a/a patients. Transfection with CD24 a and CD24 v cDNA demonstrated that the CD24 v allele can be expressed at higher efficiency than the CD24 a alleles. Thus, CD24 polymorphism is a genetic modifier for susceptibility and progression of MS in the central Ohio cohort that we studied, perhaps by affecting the efficiency of CD24 expression on the cell surface.single-nucleotide polymorphism ͉ disease susceptibility ͉ autoimmunity ͉ costimulatory molecules ͉ T lymphocytes M ultiple sclerosis (MS) is a chronic disorder in the CNS that affects Ϸ0.1% of Caucasians of northern European origin (1). The incidence of MS is increased among family members of affected individuals. The concordance rate of the identical twins can be as high as 30% (1-3). The HLA loci is perhaps the most important genetic element for MS susceptibility, because the HLA-DR2 allele has been identified as the most important susceptibility gene among Caucasians (4-10). Several additional loci have also been proposed (8-12).One of the whole-genome scans suggested a linkage disequilibrium in distal 6q (8) whose identity has not been revealed. An interesting candidate in the region is CD24 (13), which we showed to be essential for the induction of experimental autoimmune encephalomyelitis (EAE) in mice (13). CD24 is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein with expression in a variety of cell types that can participate in the pathogenesis of MS, including activated T cells (14, 15), B cells (16), macrophages (17), dendritic cells (18), and local antigen-presenting cells in the CNS, such as vascular endothelial cells, astrocytes, and microglia (our unpublished observation). It is well established that in the mouse CD24 mediates a CD28-independent costimulatory pathway that promotes activation of CD4 and CD8 T cells (16)(17)(18)(19)(20)(21). In addition, CD24 has been shown to modulate the very l...

This study is designed to characterize the signal cascades by which brain-derived neurotrophic factor (BDNF) modulates long-term memory of fear conditioning. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis of tissue homogenates taken from fear-conditioned rats showed an increase in the amygdala of BDNF protein levels and its receptor TrkB phosphorylation. Bilateral administration of a TrkB ligand scavenger TrkB IgG and a Trk-specific tyrosine kinase inhibitor K252a to the amygdala impaired fear memory, as measured with fear-potentiated startle. Fear conditioning resulted in the association of Shc and TrkB, Shc and Ras, the increase in active Ras and phosphorylation of mitogen-activated protein kinase (MAPK). Treatment of amygdala slices with BDNF for 15 min increased the levels of active Ras, and MAPK and Akt phosphorylation. BDNF-induced MAPK phosphorylation was completely abolished by MEK inhibitors, and was partially inhibited by farnesyltransferase or phosphatidylinositol-3 kinase (PI-3 kinase) inhibitors. On the other hand, BDNF-induced Akt phosphorylation was unaffected by farnesyltransferase or MEK inhibitors, but could be blocked by PI-3 kinase inhibitors. Together, these data suggest a requirement of BDNF for fear learning. The memory-enhancing effect of BDNF involves the activation of MAPK and PI-3 kinase. BDNF-induced MAPK phosphorylation in the amygdala is mediated via TrkB and the Shc-binding site. Shc binding to TrkB leads to activation of Ras, Raf, and MEK. In addition, BDNF could induce phosphorylation of MAPK via activation of PI-3 kinase.

Although the transcription factor Krüppel-like factor 5 (KLF5) plays important roles in both inflammation and cancer, the mechanism by which this factor promotes cervical carcinogenesis remains unclear. In this study, we demonstrated a potential role for tumour necrosis factor receptor superfamily member 11a (TNFRSF11a), the corresponding gene of which is a direct binding target of KLF5, in tumour cell proliferation and invasiveness. Coexpression of KLF5 and TNFRSF11a correlated significantly with tumorigenesis in cervical tissues (P < 0.05) and manipulation of KLF5 expression positively affected TNFRSF11a mRNA and protein expression. Functionally, KLF5 promoted cancer cell proliferation, migration and invasiveness in a manner dependent partly on TNFRSF11a expression. Moreover, in vivo functional TNFRSF11a-knockdown mouse studies revealed suppression of tumorigenicity and liver metastatic potential. Notably, tumour necrosis factor (TNF)-α induced KLF5 expression by activating the p38 signalling pathway and high KLF5 and TNFRSF11a expression increased the risk of death in patients with cervical squamous cell carcinoma. Our results demonstrate that KLF5 and TNFRSF11a promote cervical cancer cell proliferation, migration and invasiveness.

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