title: Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13.
abstract: IL-13 is a major Th2 cytokine that is capable of inducing inflammation, excessive mucus production, airway hyperresponsiveness, alveolar remodeling, and fibrosis in the murine lung. Although IL-13 through its binding to IL-4Ralpha/IL-13Ralpha1 uses the canonical STAT6-signaling pathway to mediate these tissue responses, recent studies have demonstrated that other signaling pathways may also be involved. Previous studies from our laboratory demonstrated that IL-13 mediates its tissue effects by inducing a wide variety of downstream genes many of which are known to be regulated by NF-kappaB. As a result, we hypothesized that NF-kappaB activation plays a critical role in the pathogenesis of IL-13-induced tissue alterations. To test this hypothesis, we compared the effects of transgenic IL-13 in mice with normal and diminished levels of NF-kappaB activity. Three pharmacologic approaches were used to inhibit NF-kappaB including 1) PS1145, a small molecule inhibitor of IkappaBalpha kinase (IKK2), 2) antennapedia-linked NF-kappaB essential modulator-binding domain (NBD) peptide (wild-type NBD), and 3) an adenoviral construct expressing a dominant-negative version of IKK2. We also crossed IL-13-transgenic mice with mice with null mutations of p50 to generate mice that overproduced IL-13 in the presence and absence of this NF-kappaB component. These studies demonstrate that all these interventions reduced IL-13-induced tissue inflammation, fibrosis and alveolar remodeling. In addition, we show that both PS1145 and wild-type NBD inhibit lung inflammatory and structural cell apoptosis. PS1145 inhibits caspase activation and up-regulates inhibitor of apoptosis protein cellular-inhibitor of apoptosis protein 1 (c-IAP-1). Therefore, NF-kappaB is an attractive target for immunotherapy of IL-13-mediated diseases.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. schapoval@som.umaryland.edu
authors.forename: Svetlana P
authors.initials: SP
authors.lastname: Chapoval
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Garawi
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lora
authors.forename: Ian
authors.initials: I
authors.lastname: Strickland
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009093:Mucus / Q000276:immunology; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D020169:Caspases; D006575:Heterocyclic Compounds, 3-Ring; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D018793:Interleukin-13; D052002:NF-kappa B p50 Subunit; D010455:Peptides; D011725:Pyridines; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C467063:NBD peptide, mouse; C456319:PS1145