Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13.

Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13. Research Abstract Details 

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Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13. Abstract Text:

Svetlana P Chapoval,Amal Al-Garawi,Jose M Lora,Ian Strickland,Bing Ma,Patty J Lee,Robert J Homer,Sankar Ghosh,Anthony J Coyle,Jack A Elias,Svetlana P Chapoval,Amal Al-Garawi,Jose M Lora,Ian Strickland,Bing Ma,Patty J Lee,Robert J Homer,Sankar Ghosh,Anthony J Coyle,Jack A Elias,

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.

Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13. Publishing Authors By Initials

SP Chapoval,A Al-Garawi,JM Lora,I Strickland,B Ma,PJ Lee,RJ Homer,S Ghosh,AJ Coyle,JA Elias,SP Chapoval,A Al-Garawi,JM Lora,I Strickland,B Ma,PJ Lee,RJ Homer,S Ghosh,AJ Coyle,JA Elias,

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Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of immunology (Baltimore, Md. : 1950)

VOLUME: 179

Page Numbers: 7030-41

Journal Abbreviation: J. Immunol.

ISSN: 0022-1767

DAY: 15

MONTH: Nov

YEAR: 2007

Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13. Information

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LANGUAGE: eng

NlmUniqueID: 2985117

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Grant and Affiliation Information for Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13.

AFFILIATION: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. schapoval@som.umaryland.edu

Country: United States

AGENCY: United States NHLBI

GRANT: HL-78744

ACRONYM: HL

MEDLINETA: J Immunol

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