01 March 2017 by Grazyna Kwapiszewska

Increased interleukin-1 levels are an early hallmark of pulmonary remodelling in Fra-2 mouse model of scleroderma


Pulmonary hypertension (PH) and pulmonary fibrosis (PF) worsen the clinical outcome of scleroderma patients. However, the factors responsible for vascular and parenchymal remodelling are still unclear. Here, we have investigated the sequence of events leading to pulmonary remodelling in SSc.


The longitudinal development and progression of SSc was studied in the Fra-2 TG mouse model. Signalling pathways and extracellular matrix protein expression were investigated in primary human pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts (PFs) after IL-1α or IL-1β stimulation. Human lung tissue and plasma samples were applied to translate our findings to SSc patients.


In Fra-2 TG mice, vascular remodelling was evident already at 8 weeks, prior to the development of pulmonary fibrosis, and accompanied by elevated IL-1α levels. IL-1 activated the JNK and p38 kinases in PASMCs and PFs, whereas NF-κB and ERK were activated in PFs and PASMCs, respectively. IL-1 stimulation downregulated collagen 1 and α-Sma, but increased the expression of IL-6 and tenascin C (TNC) in both cell types, without affecting their proliferation. Similarly, in vivo elevated IL-1α in Fra-2 TG mice was followed by increased IL-6 and TNC at 16 and 24 weeks on mRNA and protein levels concomitant with enhanced phosphorylation of STAT3. Circulating TNC levels were increased in patients with manifested lung fibrosis (mean ± SD: 61.3 ± 38.8 ng/ml) compared to healthy controls (19.2 ± 6.9 ng/ml), patients with PH (27.6 ± 8.2 ng/ml) and SSc without pulmonary fibrosis (29.5 ± 17.9 ng/ml).


Increased Fra-2/IL-1 levels exert indirect pro-fibrotic effects on resident pulmonary cells through IL-6 and TNC. Furthermore, TNC serves as a potential marker to discriminate patients with and without pulmonary fibrosis.

About the author

profile picture of Grazyna Kwapiszewska

Key Contributors

Gungl A1, Crnkovic S1,2, Biasin V2, Marsh LM2, Sahu-Osen A2, Ghanim B2,3, Klepetko W3, Odler B2, Kovacs G2,4, Eferl R5, Olschewski H4, Olschewski A1,2, Kwapiszewska G1,2. 1Department of Physiology, Medical University of Graz, Graz, Austria. 2Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria. 3Department of Surgery, Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. 4Division of Pulmonology, Medical University of Graz, Graz, Austria. 5Institute of Cancer Research of the Medical University of Vienna, Austria.

Comments (0)

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI