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Induced Suppression (induced + suppression)
Selected AbstractsInterferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responsesIMMUNOLOGY, Issue 1 2010Amit Golding Summary An adequate effector response against pathogens and its subsequent inactivation after pathogen clearance are critical for the maintenance of immune homeostasis. This process involves an initial phase of T-cell effector (Teff) activation followed by the expansion of regulatory T cells (Tregs), a unique cell population that limits Teff functions. However, significant questions remain unanswered about the mechanisms that regulate the balance between these cell populations. Using an in vitro system to mimic T-cell activation in human peripheral blood mononuclear cells (PBMC), we analysed the patterns of Treg and Teff activation, with special attention to the role of type I interferon (IFN-I). Interestingly, we found that IFN-,, either exogenously added or endogenously induced, suppressed the generation of CD4+ FoxP3HI IFN-,Neg activated Tregs (aTregs) while simultaneously promoting propagation of CD4+ FoxP3Low/Neg IFN-,Pos activated Teffs (aTeffs). We also showed that IFN-,-mediated inhibition of interleukin (IL)-2 production may play an essential role in IFN-,-induced suppression of aTregs. In order to test our findings in a disease state with chronically elevated IFN-,, we investigated systemic lupus erythematosus (SLE). Plasma from patients with SLE was found to contain IFN-I activity that suppressed aTreg generation. Furthermore, anti-CD3 activated SLE PBMCs exhibited preferential expansion of aTeffs with a very limited increase in aTreg numbers. Together, these observations support a model whereby a transient production of IFN-, (such as is seen in an early antiviral response) may promote CD4 effector functions by delaying aTreg generation, but a chronic elevation of IFN-, may tip the aTeff:aTreg balance towards aTeffs and autoimmunity. [source] Irsogladine maleate counters the interleukin-1,-induced suppression in gap-junctional intercellular communication but does not affect the interleukin-1,-induced zonula occludens protein-1 levels in human gingival epithelial cellsJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2008T. Fujita Background and Objective:, Irsogladine maleate counters gap junctional intercellular communication reduction induced by interleukin-8 or Actinobacillus actinomycetemcomitans in cultured human gingival epithelial cells. Interleukin-1, is involved in periodontal disease. Little is known, however, about the effect of interleukin-1, on intercellular junctional complexes in human gingival epithelial cells. Furthermore, irsogladine maleate may affect the actions of interleukin-1,. In this study, we examined how interleukin-1, affected gap junctional intercellular communication, connexin 43 and zonula occludens protein-1, and how irsogladine maleate modulated the interleukin-1,-induced changes in the intercellular junctional complexes in human gingival epithelial cells. Material and Methods:, Human gingival epithelial cells were exposed to interleukin-1,, with or without irsogladine maleate. Connexin 43 and zonula occludens protein-1 were examined at mRNA and protein levels by real-time polymerase chain reaction and western blotting, respectively. Gap junctional intercellular communication was determined using the dye transfer method. The expression of zonula occludens protein-1 was also confirmed by immunofluorescence. Results:, Interleukin-1, decreased connexin 43 mRNA levels, but increased zonula occludens protein-1 mRNA levels. Irsogladine maleate countered the interleukin-1,-induced reduction in gap junctional intercellular communication and connexin 43 levels. However, irsogladine maleate did not influence the increased zonula occludens protein-1 levels. Conclusion:, The effect of interleukin-1, on gap junctional intercellular communication and tight junctions of human gingival epithelial cells is different. The recovery of gap junctional intercellular communication by irsogladine maleate in the gingival epithelium may be a normal process in gingival epithelial homeostasis. [source] Melatonin protects against streptozotocin, but not interleukin-1,-induced damage of rodent pancreatic ,-cellsJOURNAL OF PINEAL RESEARCH, Issue 3 2001Annika K. Andersson In the present study, we examined whether melatonin can protect rodent pancreatic islets against streptozotocin (STZ) and interleukin-1, (IL-1,)-induced suppression of ,-cell function. Formation of free radicals, DNA damage and extensive DNA repair leading to depletion of intracellular nicotinamide adenine dinucleotide (NAD) may mediate STZ toxicity. Activation of inducible nitric oxide synthase and nitric oxide (NO) formation may cause IL-1,-induced ,-cell impairment. We also studied the effect of melatonin against STZ-induced hyperglycemia in C57BL/Ks mice. For in vitro studies, cultured rat islets were exposed to melatonin (100 ,M,1 mM) 30 min prior to STZ (0.5 mM) or IL-1, (25 U/mL) addition. After an additional 30 min incubation with STZ, islet function and NAD content were analyzed either acutely or after 18 hr of recovery in fresh culture medium. For IL-1, experiments, islets were incubated for 48 hr with the cytokine before evaluation of islet function. We found that melatonin counteracted STZ-induced inhibition of glucose metabolism and insulin release in cultured rat islets after 18 hr of recovery. Moreover, NAD levels were higher in the melatonin-treated group at this time point. Melatonin had no effect on IL-1,-induced islet inhibition of glucose oxidation or NO formation. Diabetes induced by STZ (140 mg/kg body weight; i.v.) was effectively prevented by administration of melatonin (100 mg/kg body weight; i.p.) 30 min before STZ injection. We conclude that the protective effects of melatonin against ,-cell damage may be related to interference with DNA damage and poly(ADP-ribose) polymerase (PARP) activation rather than through effects on NO generation pathways. [source] Induction of bovine articular chondrocyte senescence with oxidized low-density lipoprotein through lectin-like oxidized low-density lipoprotein receptor 1ARTHRITIS & RHEUMATISM, Issue 10 2009Satoshi Zushi Objective Findings of recent in vivo and in vitro studies suggest that oxidized low-density lipoprotein (ox-LDL) plays a role in the degeneration of cartilage. The purpose of this study was to determine whether ox-LDL induces chondrocyte senescence through binding to lectin-like ox-LDL receptor 1 (LOX-1). Methods The effects of ox-LDL on senescence of cultured bovine articular chondrocytes (BACs) were investigated by observing senescence-associated (SA) ,-galactosidase (,-gal) activity, cell proliferation activity, and telomerase activity. Telomerase activity was measured after adding LY294002 (a specific inhibitor of phosphatidylinositol 3-kinase [PI3K]) or after adding insulin-like growth factor 1 (IGF-1; an activator of PI3K) plus ox-LDL to the culture medium to elucidate the involvement of the PI3K/Akt pathway. Immunoblot analysis was used to investigate whether ox-LDL affects the phosphorylation of Akt. To ascertain whether these effects were attributable to ox-LDL binding to LOX-1, BACs were preincubated with TS-20, an anti-bovine LOX-1 blocking antibody. Results The activity of SA ,-gal was increased and the incorporation of bromodeoxyuridine into BACs was decreased by ox-LDL in a dose-dependent manner. The telomerase activity of BACs was suppressed by the addition of ox-LDL in a time- and dose-dependent manner. LY294002 suppressed the telomerase activity of BACs, and IGF-1 reversed the ox-LDL,induced suppression of telomerase activity. In addition, ox-LDL rapidly decreased the amount of phosphorylated Akt in BACs. Pretreatment of cultured BACs with TS-20 recovered these effects. Conclusion These data show that ox-LDL binding to LOX-1 induces stress-induced premature senescence of chondrocytes and results in suppression of telomerase activity by inactivating the PI3K/Akt pathway. Oxidized LDL may play an important role in the pathogenesis of osteoarthritis by inducing chondrocyte senescence. [source] G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus -induced suppression of TNF production in macrophagesCELLULAR MICROBIOLOGY, Issue 12 2006Sung O. Kim Summary Lactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus, L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-, (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR-1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte-colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR-12 and Enterococcus faecalis. By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG- and GR-1-exposed macrophages suppressed TNF production induced by E. coli - or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-Jun-N-terminal kinases (JNKs). The inhibition of JNK activation required STAT3,-mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus -triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages. [source] | |||||||||||||