Abstract
Thymic stromal lymphopoietin (TSLP) was recently identified as a master switch for Th2 responses. This study discusses the role of TSLP in pulmonary fibrosis. We show that TGF-β1 (a Fibrogenic Growth Factor) up regulates TSLP proteins in human lung fibroblasts (HFL-1) on a dose- and time-course-dependent basis. Additionally, TSLP increases fibronectin expression on a dose- (1 ng/ml to 100 ng/ml) and time-course-dependent basis concomitantly with the upregulation of pSmad2/3 and Smad4, which is the essential downstream signal regulator for TGF-β. Silencing TSLP by TSLP shRNA dramatically reverses TGF-β1-induced cellular fibrosis concomitantly with the suppression of type I TGF-β receptors and pSmad2/3. Parallel results are observed in vivo. Bleomycin-treated C57BL/6 mice show intense staining for TSLP in fibrotic lung tissue by immunohistochemistry. More importantly, Sirius red and H&E staining from bleomycin-treated mice demonstrate that transfection with TSLP shRNA (by intranasal instillation) dramatically decreases both infiltration of inflammatory cells and deposition of collagen compared to the control. Moreover, a whole-body plethysmography test showed that TSLP shRNA transgenic mice significantly attenuate the increase in airway respiratory resistance induced by bleomycin. Thus, it may be possible to use TSLP shRNA as a novel therapeutic approach for treating pulmonary fibrosis by down-regulating TGF-β signal proteins.
Highlights
Pulmonary Fibrosis (PF) is the end stage of a wide range of inflammatory lung conditions [1]
Since Thymic Stromal Lymphopoietin (TSLP) has been implicated in the pathogenesis of inflammatory diseases in recent years, it is of further interest to investigate whether TSLP regulates TGF-β1/Smad signaling
TSLP appears essential for the regulation of lung fibrosis since fibrogenic signaling is dramatically induced in lung fibroblast cells following treatment with TSLP
Summary
Pulmonary Fibrosis (PF) is the end stage of a wide range of inflammatory lung conditions [1]. It can result from a variety of causes, including lung injury, environmental particle and toxin inhalation, chemotherapy, and systemic autoimmune diseases [2]. Thymic Stromal Lymphopoietin (TSLP) is a novel IL-7-like cytokine, originally cloned from a murine thymic stromal cell line [4] It was first identified in conditioned medium supernatants of the mouse thymic stromal cell line Z210R.1 [5]. TSLP has been shown to be highly involved in the pathogenesis of inflammatory diseases [6] It is produced by epithelial cells, skin keratinocytes, stromal cells, smooth muscle cells, mast cells, and lung fibroblasts [7]. Over-expression of TSLP in transgenic mice induces spontaneous airway inflammation and atopic dermatitis [10]; little is known about the role of TSLP in regulating fibrosis in pulmonary fibrosis
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