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Introduction Thymic Stromal Lymphopoetin (TSLP) is a T helper-2 (Th2) cytokine that may be an important regulator of tissue fibrosis.¹ Rheumatoid Arthritis (RA)-associated interstitial lung disease is a fibrotic extra-articular complication associated with dysregulated adaptive immunity in the lung. In a recent study – Vassallo et al. Clin Immunol 2014;152(1–2):25–35 – we reported increased TSLP mRNA levels in the lungs of cigarette smoke-exposed, collagen induced arthritis mice with a DQ8 background.²

Objectives The purpose of this study was to explore direct molecular mechanisms by which TSLP induces fibrogenesis.

Methods We performed in vitro studies with human lung fibroblasts (Lonza) incubated with recombinant human TSLP (R&D Systems, 0–10 ng/ml) and determined TSLP-induced proliferation using a CyQuant assay, as well as collagen and fibronectin gene expression. We also investigated signaling intermediates activated by TSLP utilizing a Signal Transduction and Activator of Transcription (STAT)1–6 ELISA assay on lysates generated from TSLP stimulated fibroblasts at varying time points.

Results Human lung fibroblasts proliferate directly in response to TSLP with concentrations ≥1 ng/ml inducing a significant proliferative response compared with controls. TSLP also induced fibronectin and collagen gene expression in lung fibroblasts. Incubation with TSLP induced phosphorylation of STAT-1 and STAT-3: phosphorylation of STAT-2, as well as 4–6 was not observed. Phosphorylation of STAT-1 and 3 were observed within 30 minutes of incubation with TSLP (10 ng/ml).

Conclusions These in vitro studies demonstrate that fibroblasts are directly responsive to recombinant human TSLP which induces proliferation and matrix generation, potentially through activation of STAT-1 and 3. These observations further support a role for TSLP as a regulator of tissue fibrosis in the lung, and suggest a potential therapeutic target for the treatment of autoimmunity related fibrosis.

References

1. . Datta A, Alexander R, Sulikowski MG, Nicholson AG, Maher TM, Scotton CJ, Chambers RC. Evidence for a functional thymic stromal lymphopoietin signaling axis in fibrotic lung disease. J Immunol November 1 2013;191(9):4867–79.

2. . Vassallo R, Luckey D, Behrens M, Madden B, Luthra H, David C, Taneja V. Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin Immunol May–June 2014;152(1–2):25–35.

Disclosure of interest L. Wang: None declared, S. Wang: None declared, V. Taneja : None declared, R. Vassallo Grant/research support from: Pfizer and Bristol Myers Squibb