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31.
Regulation of alternative macrophage activation by galectin-3 总被引:3,自引:0,他引:3
MacKinnon AC Farnworth SL Hodkinson PS Henderson NC Atkinson KM Leffler H Nilsson UJ Haslett C Forbes SJ Sethi T 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(4):2650-2658
Alternative macrophage activation is implicated in diverse disease pathologies such as asthma, organ fibrosis, and granulomatous diseases, but the mechanisms underlying macrophage programming are not fully understood. Galectin-3 is a carbohydrate-binding lectin present on macrophages. We show that disruption of the galectin-3 gene in 129sv mice specifically restrains IL-4/IL-13-induced alternative macrophage activation in bone marrow-derived macrophages in vitro and in resident lung and recruited peritoneal macrophages in vivo without affecting IFN-gamma/LPS-induced classical activation or IL-10-induced deactivation. IL-4-mediated alternative macrophage activation is inhibited by siRNA-targeted deletion of galectin-3 or its membrane receptor CD98 and by inhibition of PI3K. Increased galectin-3 expression and secretion is a feature of alternative macrophage activation. IL-4 stimulates galectin-3 expression and release in parallel with other phenotypic markers of alternative macrophage activation. By contrast, classical macrophage activation with LPS inhibits galectin-3 expression and release. Galectin-3 binds to CD98, and exogenous galectin-3 or cross-linking CD98 with the mAb 4F2 stimulates PI3K activation and alternative activation. IL-4-induced alternative activation is blocked by bis-(3-deoxy-3-(3-methoxybenzamido)-beta-D-galactopyranosyl) sulfane, a specific inhibitor of extracellular galectin-3 carbohydrate binding. These results demonstrate that a galectin-3 feedback loop drives alternative macrophage activation. Pharmacological modulation of galectin-3 function represents a novel therapeutic strategy in pathologies associated with alternatively activated macrophages. 相似文献
32.
Differential roles of galectin-1 and galectin-3 in regulating leukocyte viability and cytokine secretion 总被引:4,自引:0,他引:4
Stowell SR Qian Y Karmakar S Koyama NS Dias-Baruffi M Leffler H McEver RP Cummings RD 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(5):3091-3102
Galectin-1 (Gal-1) and galectin-3 (Gal-3) exhibit profound but unique immunomodulatory activities in animals but their molecular mechanisms are incompletely understood. Early studies suggested that Gal-1 inhibits leukocyte function by inducing apoptotic cell death and removal, but recent studies show that some galectins induce exposure of the common death signal phosphatidylserine (PS) independently of apoptosis. In this study, we report that Gal-3, but not Gal-1, induces both PS exposure and apoptosis in primary activated human T cells, whereas both Gal-1 and Gal-3 induce PS exposure in neutrophils in the absence of cell death. Gal-1 and Gal-3 bind differently to the surfaces of T cells and only Gal-3 mobilizes intracellular Ca2+ in these cells, although Gal-1 and Gal-3 bind their respective T cell ligands with similar affinities. Although Gal-1 does not alter T cell viability, it induces IL-10 production and attenuates IFN-gamma production in activated T cells, suggesting a mechanism for Gal-1-mediated immunosuppression in vivo. These studies demonstrate that Gal-1 and Gal-3 induce differential responses in T cells and neutrophils, and identify the first factor, Gal-3, capable of inducing PS exposure with or without accompanying apoptosis in different leukocytes, thus providing a possible mechanism for galectin-mediated immunomodulation in vivo. 相似文献
33.
E Feuk-Lagerstedt E T Jordan H Leffler C Dahlgren A Karlsson 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(10):5592-5598
The mammalian lectin galectin-3 is a potent stimulus of human neutrophils, provided that the receptor(s) for the lectin has been mobilized to the cell surface before activation. We have recently shown that the receptors for galectin-3 are stored in intracellular mobilizable granules. Here we show supportive evidence for this in that DMSO-differentiated (neutrophil-like) HL-60 cells, which lack gelatinase and specific granules, are nonresponsive when exposed to galectin-3. Neutrophil granules were subsequently used for isolation of galectin-3 receptors by affinity chromatography. Proteins eluted from a galectin-3-Sepharose column by lactose were analyzed on SDS-polyacrylamide gels and showed two major bands of 100 and 160 kDa and a minor band of 120 kDa. By immunoblotting, these proteins were shown to correspond to CD66a (160 kDa), CD66b (100 kDa), and lysosome-associated membrane glycoprotein-1 and -2 (Lamp-1 and -2; 120 kDa). The unresponsive HL-60 cells lacked the CD66 Ags but contained the Lamps, implying that neutrophil CD66a and/or CD66b may be the functional galectin-3 receptors. This conclusion was supported by the subcellular localization of the CD66 proteins to the gelatinase and specific granules in resting neutrophils. 相似文献
34.
Oberg CT Blanchard H Leffler H Nilsson UJ 《Bioorganic & medicinal chemistry letters》2008,18(13):3691-3694
A series of O2 and O3-derivatized methyl beta-d-talopyranosides were synthesized and evaluated in vitro as inhibitors of the galactose-binding galectin-1, -2, -3, -4 (N- and C-terminal domains), 8 (N-terminal domain), and 9 (N-terminal domain). Galectin-4C and 8N were found to prefer the d-talopyranose configuration to the natural ligand d-galactopyranose configuration. Derivatization at talose O2 and/or O3 provided selective submillimolar inhibitors for these two galectins. 相似文献
35.
36.
Derivatives of N-acetyllactosamine carrying structurally diverse thioureido groups at galactose C3 were prepared from a C3'-azido N-acetyllactosamine derivative in a three-step reaction sequence involving azide reduction and isothiocyanate formation by thiophosgene treatment of the C3-amine, followed by reaction of the isothiocyanate with a panel of amines. Evaluation of the N-acetyllactosamine thioureas as inhibitors against galectins-1, 3, 7, 8N (N-terminal domain), and 9N (N-terminal domain) revealed thiourea-mediated affinity enhancements for galectins-1, 3, 7, and 9N. In particular, good inhibitors were discovered against galectin-7 and 9N (K(d) 23 and 47 microM, respectively, for a 3-pyridylmethylthiourea derivative), which represents more than an order of magnitude affinity enhancement over the parent natural N-acetyllactosamine. 相似文献
37.
38.
Leffler CW Parfenova H Basuroy S Jaggar JH Umstot ES Fedinec AL 《American journal of physiology. Heart and circulatory physiology》2011,300(2):H440-H447
Hydrogen sulfide (H2S) is a gaseous signaling molecule that appears to be involved in numerous biological processes, including regulation of blood pressure and vascular tone. The present study is designed to address the hypothesis that H2S is a functionally significant, endogenous dilator in the newborn cerebrovascular circulation. In vivo experiments were conducted using newborn pigs with surgically implanted, closed, cranial windows. Topical application of H2S concentration-dependently (10(-6) to 2×10(-4) M) dilated pial arterioles. This dilation was blocked by glibenclamide (10(-6) M). L-cysteine, the substrate of the H2S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), also dilated pial arterioles. The dilation to L-cysteine was blocked by the CSE inhibitor d,l-propargylglycine (PPG, 10 mM) but was unaffected by the CBS inhibitor amino-oxyacetate (AOA, 1 mM). Western blots detected CSE, but not CBS, in cerebral microvessels, whereas CBS is detected in brain parenchyma. Immunohistological CSE expression is predominantly vascular while CBS is expressed mainly in neurons and astrocytes. L-cysteine (5 mM) increased H2S concentration in cerebrospinal fluid (CSF), measured by GC-MS, from 561±205 to 2,783±818 nM before but not during treatment with PPG (1,030±70 to 622±78 nM). Dilation to hypercapnia was inhibited by PPG but not AOA. Hypercapnia increased CSF H2S concentration from 763±243 to 4,337±1789 nM before but not during PPG treatment (357±178 vs. 425±217 nM). These data show that H2S is a dilator of the newborn cerebral circulation and that endogenous CSE can produce sufficient H2S to decrease vascular tone. H2S appears to be a physiologically significant dilator in the cerebral circulation. 相似文献
39.
Kanu A Leffler CW 《American journal of physiology. Heart and circulatory physiology》2011,301(6):H2482-H2487
Arachidonic acid (AA) and prostaglandin (PG) E(2) stimulate carbon monoxide (CO) production, and AA metabolism is known to be associated with the generation of reactive oxygen species (ROS). This study was conducted to address the hypothesis that CO and/or ROS mediate cerebrovascular dilation in newborn pigs. Experiments were performed on anesthetized newborn pigs with closed cranial windows. Different concentrations of AA (10(-8)-10(-6) M), PGE(2) (10(-8)-10(-6) M), iloprost (10(-8)-10(-6) M), and their vehicle (artificial cerebrospinal fluid) were given. Piglets with PGE(2) and iloprost received indomethacin (5 mg/kg iv) to inhibit cyclooxygenase. AA, PGE(2), and iloprost caused concentration-dependent increases in pial arteriolar diameter. The effects of both AA and PGE(2) in producing cerebral vascular dilation and associated CO production were blocked by the heme oxygenase inhibitor chromium mesoporphyrin (2 × 10(-5) M), but not by the prostacyclin analog, iloprost. ROS inhibitor tempol (SOD mimetic) (1 × 10(-5) M) and the H(2)O(2) scavenger catalase (1,000 U/ml) also do not block these vasodilator effects of AA and PGE(2). Heme-L-lysinate-induced cerebrovascular dilation and CO production was blocked by chromium mesoporphyrin. Hypoxanthine plus xanthine oxidase, a combination that is known to generate ROS, caused pial arteriolar dilation and CO production that was inhibited by tempol and catalase. These data suggest that AA- and PGE(2)-induced cerebral vascular dilation is mediated by CO, independent of ROS. 相似文献
40.
Maren Ziegler Shannon K. FitzPatrick Ingo Burghardt Katie L. Liberatore A. Joshua Leffler Cristina Takacs-Vesbach Ursula Shepherd 《Coral reefs (Online)》2014,33(4):1085-1099
In this study, we examined two non-scleractinian taxa, the rare nudibranch Phyllodesmium lizardensis and Bayerxenia sp., the octocoral on which the nudibranch lives and feeds, to investigate the effect of experimental heat stress on their symbioses with Symbiodinium. Bleaching has not been studied in nudibranchs. Bayerxenia sp. belongs to the alcyonacea family Xeniidae, members of which are known to be heat sensitive, but the genus has never been subject to heat stress experiments or bleaching observations. While qPCR did not reveal any changes to the symbiont community composition, the two host species responded differently to increased temperature. There were changes in the relative proportion of tissue types in Bayerxenia sp., but these were not attributable to the temperature treatment. Bayerxenia sp. exhibited no changes in cellular structure (apoptosis or cell necrosis), or symbiont functioning, cell size, density, or cladal community structure. On the other hand, the host, P. lizardensis, experienced tissue loss and symbiont densities decreased significantly with the majority of the remaining symbiont cells significantly degenerated after the heat stress. This decrease did not influence symbiont community composition, symbiont cell size, or photosynthetic efficiency. While the bleaching process in nudibranchs was demonstrated for the first time, the physiological and molecular pathways leading to this response still require attention. 相似文献