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B Activation Reduces the Tissue Effects of Transgenic IL-131
* Section of Pulmonary and Critical Care Medicine,
Section of Immunobiology, and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520; and
Millennium Pharmaceuticals, Cambridge, MA 02142
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-4R
/IL-13R1 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-
B. As a result, we hypothesized that NF-B 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-B activity. Three pharmacologic approaches were used to inhibit NF-B including 1) PS1145, a small molecule inhibitor of IB kinase (IKK2), 2) antennapedia-linked NF-B 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-B 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-B is an attractive target for immunotherapy of IL-13-mediated diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL-64242, HL-78744, HL-66571, HL-56389 awarded to J.A.E.
2 Address correspondence and reprint requests to Dr. Svetlana P. Chapoval at the current address: Department of Microbiology and Immunology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, MD 21201. E-mail address: schapoval{at}som.umaryland.edu
3 Current address: Division of Respiratory Diseases and Allergy, McMaster University, Hamilton, Ontario, Canada.
4 Current address: Department of Inflammation, Autoimmunity and Transplantation, Roche Pharmaceuticals, Palo Alto, CA 94304.
5 Current address: Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878.
6 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; MMP, matrix metalloprotease; IKK, IB kinase; NEMO, NF-B essential modulator; NBD, NEMO-binding domain; DN, dominant negative; tg, transgenic; DOX, doxycyclin; KO, knockout; WT, wild type; w.o., week old; CMC, carboxymethylcellulose; BAL, bronchoalveolar lavage; PAS, periodic-acid Schiff; PenH, enhanced pause; IAP, inhibitor of apoptosis protein; rm, recombinant mouse; iIL-13, inducible IL-13; cIL-13, constitutive IL-13.
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