Regulation of multi-organ inflammation in the regulatory T cell-deficient scurfy mice

Scurfy mice display the most severe form of multi-organ inflammation due to total lack of the CD4+Foxp3+ regulatory T cells (Treg) resulted from a mutation of the X-linked transcription factor Foxp3. A large repertoire of Treg-suppressible, inflammation-inducing T cells was demonstrated by adoptive transfer experiments using Rag1-/- mice as recipients and by prolongation of lifespan through breeding with Faslpr/lpr mutant. Inflammation in the ear, eyes, skin, tail, salivary glands, lungs, stomach, pancreas, liver, small intestine, colon, skeletal muscle, and accessory reproductive organs are identified. Genetic and cellular regulations of specific organ inflammation are described. Sf mice may be useful for the identification of organ-specific antigens and Treg capable of suppressing inflammation in an organ-specific manner. Sf mice are also useful to determine the important inflammation process at the checkpoint after Treg regulation using genetic analysis through breeding

Breaking Tolerance to Double Stranded DNA, Nucleosome, and Other Nuclear Antigens Is Not Required for the Pathogenesis of Lupus Glomerulonephritis

In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti–double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non–anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus

Effect of total flavones of buckwheat flowers and leaves on protein tyrosine phosphatase 1B expression in type 2 diabetic rats

The total flavone content was obtained from flowers and leaf of buckwheat (Fagopyrum esculentum Moench) by heating reflux method. The effects of the total flavone extract on the protein tyrosine phosphatase 1B (PTP1B) expression in type 2 diabetic rats were evaluated by immunofluorescence, western blotting and real-time quantitative PCR. The results suggested that the total flavone fraction from buckwheat flowers and leaves can significantly decrease the PTP1B expression in liver.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Effect of total flavones of buckwheat flowers and leaves on protein tyrosine phosphatase 1B expression in type 2 diabetic rats

The total flavone content was obtained from flowers and leaf of buckwheat (Fagopyrum esculentum Moench) by heating reflux method. The effects of the total flavone extract on the protein tyrosine phosphatase 1B (PTP1B) expression in type 2 diabetic rats were evaluated by immunofluorescence, western blotting and real-time quantitative PCR. The results suggested that the total flavone fraction from buckwheat flowers and leaves can significantly decrease the PTP1B expression in liver.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Studies of the Effect of Cyclosporine in Psoriasis In Vivo: Combined Effects on Activated T Lymphocytes and Epidermal Regenerative Maturation

Cyclosporine (CSA) decreases lymphokine synthesis and keratinocyte proliferation in vitro, but its in vivo mechanism of action in treating recalcitrant psoriasis is incompletely understood. Ten psoriasis patients were treated with CSA (2–7.5mg/kg/d) with clinical improvement in nine of 10 patients. Skin biopsies before and after1–3 months of CSA treatment were studied for evidence of immune and keratinocyte activation using immunoperoxidase and Northern blotting analysis. The number of activated, IL-2 receptor+ T cells in plaques after CSA treatment was reduced in all patients by a mean of 60%. Seven of 10 patients showed a decrease in keratinocyte HLA-DR expression; five of seven showed a decrease in gamma-IP-10 immunoreactivity, suggesting decline in gamma interferon levels in plaques after CSA therapy. We studied the effect of CSA treatment in vivo on TGFα IL-6 and keratin K16 expression, three markers of keratinocyte growth activation. Expression of keratinocyte TGFα and IL-6,which are elevated in active psoriatic epidermis,did not change in these patients after CSA treatment. The majority of patients (five of eight) continued to express the suggest that the predominant direct mechanism of action of Cyclosporine in vivo is a diminution of T-cell activation in plaques, with attendant decreased lymphokine production

14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β

[[abstract]]Background: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings: In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding. Significance:Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion