title: Minocycline blocks asthma-associated inflammation in part by interfering with the T cell receptor-nuclear factor κB-GATA-3-IL-4 axis without a prominent effect on poly(ADP-ribose) polymerase.
abstract: Minocycline 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-κB 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-κB was linked to a complete blockade of TCR-stimulated GATA-3 expression, a pivotal transcription factor for IL-4 expression. Minocycline also reduced TNF-α-mediated NF-κB 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-κB activation, GATA-3 expression, and subsequent IL-4 production.
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. anaura@lsuhsc.edu
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Naura
authors.forename: Hogyoung
authors.initials: H
authors.lastname: Kim
authors.forename: Jihang
authors.initials: J
authors.lastname: Ju
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.forename: Joaquin
authors.initials: J
authors.lastname: Jordan
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Catling
authors.forename: Bashir M
authors.initials: BM
authors.lastname: Rezk
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.forename: Kusma
authors.initials: K
authors.lastname: Pyakurel
authors.forename: Abdelmetalab F
authors.initials: AF
authors.lastname: Tarhuni
authors.forename: Mohammad Q
authors.initials: MQ
authors.lastname: Abughazleh
authors.forename: Youssef
authors.initials: Y
authors.lastname: Errami
authors.forename: Mourad
authors.initials: M
authors.lastname: Zerfaoui
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
mesh_terms: D000818:Animals; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D016328:NF-kappa B / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007155:Immunologic Factors; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007073:Immunoglobulin E; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008911:Minocycline