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lüll Minocycline blocks asthma-associated inflammation in part by interfering with the T cell receptor-nuclear factor kappaB-GATA-3-IL-4 axis without a prominent effect on poly(ADP-ribose) polymerase Naura AS; Kim H; Ju J; Rodriguez PC; Jordan J; Catling AD; Rezk BM; Abd Elmageed ZY; Pyakurel K; Tarhuni AF; Abughazleh MQ; Errami Y; Zerfaoui M; Ochoa AC; Boulares AHJ Biol Chem 2013[Jan]; 288 (3): 1458-68Minocycline protects against asthma independently of its antibiotic function and was recently reported as a potent poly(ADP-ribose) polymerase (PARP) inhibitor. In an animal model of asthma, a single administration of minocycline conferred excellent protection against ovalbumin-induced airway eosinophilia, mucus hypersecretion, and Th2 cytokine production (IL-4/IL-5/IL-12(p70)/IL-13/GM-CSF) and a partial protection against airway hyperresponsiveness. These effects correlated with pronounced reduction in lung and sera allergen-specific IgE. A reduction in poly(ADP-ribose) immunoreactivity in the lungs of minocycline-treated/ovalbumin-challenged mice correlated with decreased oxidative DNA damage. The effect of minocycline on PARP may be indirect, as the drug failed to efficiently block direct PARP activation in lungs of N-methyl-N'-nitro-N-nitroso-guanidine-treated mice or H(2)O(2)-treated cells. Minocycline blocked allergen-specific IgE production in B cells potentially by modulating T cell receptor (TCR)-linked IL-4 production at the mRNA level but not through a modulation of the IL-4-JAK-STAT-6 axis, IL-2 production, or NFAT1 activation. Restoration of IL-4, ex vivo, rescued IgE production by minocycline-treated/ovalbumin-stimulated B cells. IL-4 blockade correlated with a preferential inhibition of the NF-kappaB activation arm of TCR but not GSK3, Src, p38 MAPK, or ERK1/2. Interestingly, the drug promoted a slightly higher Src and ERK1/2 phosphorylation. Inhibition of NF-kappaB was linked to a complete blockade of TCR-stimulated GATA-3 expression, a pivotal transcription factor for IL-4 expression. Minocycline also reduced TNF-alpha-mediated NF-kappaB activation and expression of dependent genes. These results show a potentially broad effect of minocycline but that it may block IgE production in part by modulating TCR function, particularly by inhibiting the signaling pathway, leading to NF-kappaB activation, GATA-3 expression, and subsequent IL-4 production.|Animals[MESH]|Asthma/complications/*drug therapy/genetics/immunology[MESH]|GATA3 Transcription Factor/agonists/*genetics/immunology[MESH]|Gene Expression Regulation/drug effects[MESH]|Immunoglobulin E/genetics/immunology[MESH]|Immunologic Factors/pharmacology/*therapeutic use[MESH]|Inflammation/complications/*drug therapy/genetics/immunology[MESH]|Interleukin-4/antagonists & inhibitors/*genetics/immunology[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Minocycline/pharmacology/*therapeutic use[MESH]|NF-kappa B/agonists/*genetics/immunology[MESH]|Poly (ADP-Ribose) Polymerase-1[MESH]|Poly(ADP-ribose) Polymerases/genetics/immunology[MESH]|Receptors, Antigen, T-Cell/antagonists & inhibitors/*genetics/immunology[MESH]|Signal Transduction/drug effects[MESH] |