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  • 1
    ISSN: 0014-5793
    Keywords: Cell differentiation ; Dexamethasone ; Eicosanoid inhibition ; Lipocortin expression
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract As a putative mediator of inflammation interleukin-1 has been implicated in the recruitment of leukocytes during the early stages of the inflammatory reaction. In the present report we have investigated the release of endogenous IL-1 in the rat zymosan pleurisy and in the mouse zymosan peritonitis. In both cases the release of the cytokine was maximal 4 hours after zymosan injection and appeared to be time-related to neutrophil migration into the inflammatory site. The effect ofin vivo treatment with dexamethasone in rat pleurisy and with polyclonal anti-murine IL-1β antibody in mouse peritonitis was also assessed. The steroid reduced both cell migration and the release of IL-1-like activity as well as the formation of exudate and the release of eicosanoids. The anti-IL-1β serum inhibited selectively the number of neutrophil that migrated to the inflamed site (∼40%) and the IL-1 activity recovered in (∼70%) the exudate.In vitro incubation of the inflammatory exudate with polyclonal anti-murine IL-1α or anti-murine IL-1β sera allowed the identification of the IL-1 species present. In the rat pleurisy IL-1 biological activity was mainly due to the α species, whereas IL-1β was the only species apparently present in the mouse peritoneal exudate.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-0778
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Annexin-1 (ANXA1, lipocortin 1) is a pleiotrophic protein produced by many cell types including peripheral blood leucocytes. Although it has been shown to inhibit ‘macroscopic’ inflammatory processes in animal models, its direct effects on antigen-activated human T cells have not been studied.Objective To test the hypothesis that ANXA1-derived peptides inhibit antigen-driven prototype Th1 and Th2-type human T cell responses of clinical relevance and lectin-driven responses in vitro.Methods Peripheral blood mononuclear cells (PBMC) were isolated from 14 atopic subjects sensitized to house dust mite allergen (Dermatophagoides pteronyssinus, Der p) and purified protein derivative (PPD) of Mycobacterium tuberculosis. PBMC (1 × 106/mL) were cultured with phytohaemagglutinin (PHA; 5 µg/mL; 4 days), Der p (25 µg/mL; 6 days), PPD (10 µg/mL, 6 days) or medium control. Two ANXA1-derived peptides, Ac2–26 and AF-2 (5–500 µm), were assessed for possible inhibition of PHA-and antigen-induced T cell proliferation (measured by 3H-thymidine uptake), while Ac2–26 was assessed for inhibition of Der p-induced interleukin (IL)−5 release and PPD-induced interferon-γ (IFN-γ) release (measured by ELISA). Comparison was made with dexamethasone as an established inhibitory control. Endogenous production by PBMC of cell surface-associated and intracellular ANXA1 in response to PHA, Der p and PPD in the presence and absence of dexamethasone was measured by specific ELISA.Results Both PHA- and antigen-induced T cellular proliferation were inhibited by dexamethasone. Although neither ANXA1-derived peptide significantly altered PHA-induced proliferation, both effected concentration-dependent reductions in antigen-induced proliferation, Ac2–26 being the more potent. Peptides of identical amino acid composition to Ac2–26 and AF-2, but of random sequence, were ineffective at equivalent concentrations. In addition, Ac2–26 and dexamethasone inhibited Der p-induced IL-5 release and PPD-induced IFN-γ release in a concentration-dependent fashion. Endogenous ANXA1 was detectable in PBMC, but at concentrations approximately 104-fold lower, in molar terms, than the effective concentrations of the exogenously added, ANXA1-derived inhibitory peptides. Endogenous production was not significantly altered by any of the T cell stimuli employed in this study, in the presence or absence of dexamethasone.Conclusion In prototype Th1 and Th2-type human T cell responses, ANXA1-derived peptides can inhibit antigen-driven cellular proliferation and cytokine production.
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  • 5
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Annexin 1 (ANXA1) is a key mediator of the inhibitory effects of glucocorticoids on adrenocorticotropic hormone (ACTH) release, which develop within 1–2 h of a steroid challenge. Our previous studies, which showed that (i) ANXA1 is expressed principally by the nonsecretory folliculo-stellate cells in the pituitary gland; (ii) glucocorticoids cause the exportation of ANXA1 from these cells; and (iii) corticotrophs express specific ANXA1 binding sites, led us to propose that ANXA1 serves as a paracrine or juxtacrine mediator of glucocorticoids. To address this hypothesis, we examined ANXA1-dependent glucocorticoid actions in co-cultures of murine corticotroph (AtT20 clone D1) and folliculo-stellate (TtT/GF) cell lines. ANXA1 mRNA and protein were found in abundance in TtT/GF cells but neither was detectable in the AtT20 cells. AtT20 cells (alone and in co-culture with TtT/GF cells) responded to corticotropin-releasing hormone (CRH) (0.1–1 µm) with increased ACTH release. The CRH-stimulated release of ACTH from AtT20 cells cultured alone was unaffected by preincubation with dexamethasone (Dex, 100 nm); by contrast, in co-cultures of AtT20 and TtT/GF cells, the steroid readily inhibited the secretory response to CRH. The effects of Dex on ACTH release were mimicked by N-terminal ANXA1 fragments (ANXA1Ac2−26, 2 µg/ml and ANXA11-188, 0.1 ng/ml) and reversed by mifepristone (1 µm) and by an antisense oligodeoxynucleotide (ODN) to ANXA1 (50 nm) but not by control ODNs. The antisense ODN also specifically blocked the Dex-induced externalization of ANXA1 from TtT/GF cells. Immunofluorescence imaging of the co-cultures localized the exported protein to the vicinity of the AtT20 cells and identified ANXA1 binding sites on these cells. These results provide functional and histological evidence to support our premise that the early inhibitory effects of glucocorticoids on ACTH release are dependent upon paracrine/juxtacrine actions of ANXA1 derived from folliculo-stellate cells.
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  • 6
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Our previous studies have identified a role for annexin 1 (ANXA1), a protein produced by the pituitary folliculostellate cells, as a paracrine/juxtacrine mediator of the acute regulatory effects of glucocorticoids on the release of adrenocorticotropic hormone and other pituitary hormones. In the present study, we focused on the secretion of thyroid stimulating hormone (TSH) and luteinizing hormone (LH) and used a battery of ANXA1-derived peptides to identify the key domains in the ANXA1 molecule that are critical to the inhibition of peptide release. In addition, as ANXA1 is a substrate for protein kinase C (PKC) and tyrosine kinase, we examined the roles of these kinases in the manifestation of the ANXA1-dependent inhibitory actions of dexamethasone on TSH and LH release. Dexamethasone suppressed the forskolin-induced release of TSH and LH from rat anterior pituitary tissue in vitro. Its effects were mimicked by human recombinant ANXA1 (hrANXA1) and a truncated protein, ANXA11-188. ANXA1Ac2−26, also suppressed stimulated peptide release but it lacked both the potency and the efficacy of the parent protein. Shorter N-terminal ANXA1 sequences were without effect. The PKC inhibitor PKC19-36 abolished the inhibitory actions of dexamethasone on the forskolin-evoked release of TSH and LH; it also attenuated the inhibitory actions of ANXA1Ac2−26. Similar effects were produced by annexin 5 (ANXA5) which sequesters PKC in other systems. By contrast, the tyrosine kinase inhibitors, p60v-src (137–157) and genistein, had no effect on the secretion of TSH or LH alone or in the presence of forskolin and/or dexamethasone. Dexamethasone caused the translocation of a tyrosine-phosphorylated species of ANXA1 to the surface of pituitary cells. The total amount of ANXA1 exported from the cells in response to the steroid was unaffected by tyrosine kinase blockade. However, the degree of tyrosine-phosphorylation of the exported protein was markedly reduced by genistein. These results suggest that (i) the ANXA1-dependent inhibitory actions of dexamethasone on the release of TSH and LH require PKC and sequences in the N-terminal domain of ANXA1, but are independent of tyrosine kinase, and (ii) while dexamethasone induces the cellular exportation of a tyrosine-phosphorylated species of ANXA1, tyrosine phosphorylation per se is not critical to the steroid-induced passage of ANXA1 across the membrane.
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