Interleukin-15 attenuates transforming growth factor-β1-induced myofibroblast differentiation in human fetal lung fibroblasts.
OBJECTIVE
Fibroproliferative diseases are common causes of morbidity and mortality. Interleukin-15 (IL-15) is a pleiotropic cytokine with multiple effects on cells of the immune system. Although IL-15 is also expressed in mesenchymal cells, its effects on the development of fibrosis are unknown. We have previously described an association between serum IL-15 levels and the extent of pulmonary fibrosis in the connective tissue disease systemic sclerosis, suggesting that IL-15 may have profibrotic effects. To test this hypothesis, we studied the effects of IL-15 on myofibroblast differentiation, an in vitro model of fibrosis development.


METHODS
We used human fetal lung fibroblasts for the cytokine stimulation. As a marker of myofibroblast differentiation, α-smooth muscle actin (α-SMA) was analyzed by western blot and quantitative real-time PCR. The well-known profibrotic cytokine, transforming growth factor-β1(TGF-β1), was used for comparison, and TGF-β signaling paths were also studied.


RESULTS
IL-15 did not induce α-SMA expression, a marker for myofibroblast differentiation. Unexpectedly, IL-15 counteracted TGF-β1-mediated α-SMA expression. Moreover, TGF-β1-induced expression of collagen, fibronectin and connective tissue growth factor was attenuated by addition of IL-15. There was no effect of IL-15 on early events in the TGF-β signaling cascades.


CONCLUSIONS
IL-15 has anti-fibrotic properties that, speculatively however, may be insufficient in systemic sclerosis.
Wuttge
Dirk M
DM
Department of Clinical Sciences, Lund, Section of Rheumatology, Lund University, Lund, Sweden. dirk.wuttge@med.lu.se
Wildt
Marie
M
Scheja
Agneta
A
Westergren-Thorsson
Gunilla
G
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D019409:Interleukin-15 / Q000097:blood / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000196:embryology*; D058628:Myofibroblasts / Q000166:cytology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
C541116:ACTA2 protein, human; D000199:Actins; D017931:DNA Primers; D019409:Interleukin-15; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1