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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 1, July, 2001 60-68

Activation of the TGF-beta /Activin-Smad2 Pathway during Allergic Airway Inflammation

Alexander Rosendahl, Daniella Checchin, Thomas E. Fehniger, Peter ten Dijke, Carl-Henrik Heldin, and Paschalis Sideras

Departments of Molecular Sciences and Biosciences, AstraZeneca R&D Lund, Lund, Sweden; Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Ludwig Institute for Cancer Research, Uppsala, Sweden; and Department of Immunology, BioMedical Center, Lund University, Lund, Sweden

Changes in the levels of transforming growth factor (TGF)-beta cytokines or receptors observed during the progression of several inflammatory and fibrotic disorders have been used to implicate these cytokines in the pathophysiology of these diseases. Although correlative, these studies were inconclusive because they were unable to demonstrate actual continuous TGF-beta -mediated signaling in the involved tissues. We reasoned that the phosphorylation state and subcellular localization of Smad2, the intracellular effector of TGF-beta /activin-mediated signaling, could be used as a marker of active signaling mediated by these cytokines in situ. We therefore used an experimental model of ovalbumin-induced allergic airway inflammation and were able to demonstrate a dramatic increase in the numbers of bronchial epithelial, alveolar, and infiltrating inflammatory cells expressing nuclear phosphorylated Smad2 within the allergen-challenged lungs. This was accompanied by strong upregulation of the activin receptor ALK-4/ActR-IB and redistribution of the TGF-beta responsive ALK-5/Tbeta R-I. Although levels of TGF-beta 1, TGF-beta 2, and TGF-beta 3 messenger RNA (mRNA) were marginally altered, the level of activin mRNA was strongly upregulated during the inflammatory response. Our data illustrate the usefulness of antiphosphorylated Smad antibodies in demonstrating active TGF- beta /activin-mediated signaling in vivo and strongly suggest that activin/Smad-mediated signaling could be a critical contributor in the pathophysiology of allergic pulmonary diseases.

Abbreviations: activin receptor, ActR; activin receptor-like kinase, ALK; bone morphogenic protein, BMP; complementary DNA, cDNA; Earle's balanced salt solution, EBSS; extracellular matrix, ECM; immunoglobulin, Ig; messenger RNA, mRNA; ovalbumin, OVA; phosphate-buffered saline, PBS; receptor-regulated Smad protein, R-Smad; reverse transcriptase/polymerase chain reaction, RT-PCR; transforming growth factor, TGF; TGF-beta receptor, Tbeta R; T helper, Th.




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