The Journal of Experimental Medicine
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/151/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 151-158

Original Article

Blockade of Transforming Growth Factor β/Smad Signaling in T Cells by Overexpression of Smad7 Enhances Antigen-Induced Airway Inflammation and Airway Reactivity

Atsuhito Nakaoa, Satoshi Miikeb, Masahiko Hatanoc, Ko Okumuraa, Takeshi Tokuhisac, Chisei Raa, and Itsuo Iwamotob

a Allergy Research Center, Juntendo University, School of Medicine, Tokyo 113-8421, Japan
b Department of Medicine II, School of Medicine,
c Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Allergy Research Center, Juntendo University, School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.81-3-5802-1591

Transforming growth factor (TGF)-β has been implicated in immunosuppression. However, it remains obscure whether regulation of T cells by TGF-β contributes to the immunosuppression in vivo. To address this issue, we developed transgenic mice expressing Smad7, an intracellular antagonist of TGF-β/Smad signaling, selectively in mature T cells using a plasmid construct coding a promoter element (the distal lck promoter) that directs high expression in peripheral T cells. Peripheral T cells were not growth inhibited by TGF-β in Smad7 transgenic mice. Although Smad7 transgenic mice did not spontaneously show a specific phenotype, antigen-induced airway inflammation and airway reactivity were enhanced in Smad7 transgenic mice associated with high production of both T helper cell type 1 (Th1) and Th2 cytokines. Thus, blockade of TGF-β/Smad signaling in mature T cells by expression of Smad7 enhanced airway inflammation and airway reactivity, suggesting that regulation of T cells by TGF-β was crucial for negative regulation of the inflammatory (immune) response. Our findings also implicated TGF-β/Smad signaling in mature T cells as a regulatory component of allergic asthma.

Key Words: signaling • inhibitor • asthma • mouse • eosinophils

Abbreviations used in this paper: AHR, airway hyperresponsiveness; APTI, airway pressure–time index; B6, CB57L/6; BAL, bronchoalveolar lavage; BALF, BAL fluid; hGH, human growth hormone; Tg, transgenic; Wt, wild-type.

A. Nakao and S. Miike contributed equally to this work.

© 2000 The Rockefeller University Press


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