Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity.
Transforming growth factor (TGF)-beta has been implicated in immunosuppression. However, it remains obscure whether regulation of T cells by TGF-beta contributes to the immunosuppression in vivo. To address this issue, we developed transgenic mice expressing Smad7, an intracellular antagonist of TGF-beta/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-beta 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-beta/Smad signaling in mature T cells by expression of Smad7 enhanced airway inflammation and airway reactivity, suggesting that regulation of T cells by TGF-beta was crucial for negative regulation of the inflammatory (immune) response. Our findings also implicated TGF-beta/Smad signaling in mature T cells as a regulatory component of allergic asthma.
Nakao
A
A
Allergy Research Center, Juntendo University, School of Medicine, Tokyo 113-8421, Japan. anakao@med.untendo.ac.jp
Miike
S
S
Hatano
M
M
Okumura
K
K
Tokuhisa
T
T
Ra
C
C
Iwamoto
I
I
D000818:Animals; D001249:Asthma / Q000209:etiology*; D001402:B-Lymphocytes / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D051906:Smad7 Protein; D013601:T-Lymphocytes / Q000502:physiology*; D014132:Trachea / Q000473:pathology*; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016207:Cytokines; D004268:DNA-Binding Proteins; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D010047:Ovalbumin