Research Articles (Biochemistry)

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Browsing Research Articles (Biochemistry) by Subject "Anti-inflammatory agents"

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    A fully dissociated compound of plant origin for inflammatory gene repression
    (PNAS, 2005-11) De Bosscher, Karolien; Van den Berghe, Wim; Beck, Ilse M. E.; Van Molle, Wim; Hennuyer, Nathalie; Hapgood, Janet; Liber, Claude; Staels, Bart; Louw, Ann; Haegeman, Guy
    The identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of GR are mainly associated with undesirable side effects, its negative interference with the activity of transcription factors, such as NF-κB, greatly contributes to its antiinflammatory and immune-suppressive capacities. In the present study, we found that Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of GR-binding ligands, does mediate gene-inhibitory effects by activating GR. We demonstrate that CpdA exerts an antiinflammatory potential by down-modulating TNF-induced proinflammatory gene expression, such as IL-6 and E-selectin, but, interestingly, does not at all enhance glucocorticoid response element-driven genes or induce GR binding to glucocorticoid response element-dependent genes in vivo. We further show that the specific gene-repressive effect of CpdA depends on the presence of functional GR, displaying a differential phosphorylation status with CpdA as compared with dexamethasone treatment. The antiinflammatory mechanism involves both a reduction of the in vivo DNA-binding activity of p65 as well as an interference with the transactivation potential of NF-κB. Finally, we present evidence that CpdA is as effective as dexamethasone in counter-acting acute inflammation in vivo and does not cause a hyperglycemic side effect. Taken together, this compound may be a lead compound of a class of antiinflammatory agents with fully dissociated properties and might thus hold great potential for therapeutic use. © 2005 by The National Academy of Sciences of the USA.
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    The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor
    (PLoS, 2014-05-19) Govender, Yashini; Avenant, Chanel; Verhoog, Nicolette J. D.; Ray, Roslyn M.; Grantham, Nicholas J.; Africander, Donita; Hapgood, Janet P.
    Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4–20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.