Abstract
One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFβ). TGFβ is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1β (IL1β) can influence the severity of fibrosis, however much less is known about the direct effects on fibroblasts. Using lung and dermal fibroblasts, we have investigated the effects of IL1β, TGFβ1, and IL1β in combination with TGFβ1 on myofibroblast formation, collagen synthesis and collagen modification (including prolyl hydroxylase, lysyl hydroxylase and lysyl oxidase), and matrix metalloproteinases (MMPs). We found that IL1β alone has no obvious pro-fibrotic effect on fibroblasts. However, IL1β is able to inhibit the TGFβ1-induced myofibroblast formation as well as collagen synthesis. Glioma-associated oncogene homolog 1 (GLI1), the Hedgehog transcription factor that is involved in the transformation of fibroblasts into myofibroblasts is upregulated by TGFβ1. The addition of IL1β reduced the expression of GLI1 and thereby also indirectly inhibits myofibroblast formation. Other potentially anti-fibrotic effects of IL1β that were observed are the increased levels of MMP1, −2, −9 and −14 produced by fibroblasts exposed to TGFβ1/IL1β in comparison with fibroblasts exposed to TGFβ1 alone. In addition, IL1β decreased the TGFβ1-induced upregulation of lysyl oxidase, an enzyme involved in collagen cross-linking. Furthermore, we found that lung and dermal fibroblasts do not always behave identically towards IL1β. Suppression of COL1A1 by IL1β in the presence of TGFβ1 is more pronounced in lung fibroblasts compared to dermal fibroblasts, whereas a higher upregulation of MMP1 is seen in dermal fibroblasts. The role of IL1β in fibrosis should be reconsidered, and the differences in phenotypical properties of fibroblasts derived from different organs should be taken into account in future anti-fibrotic treatment regimes.
Highlights
Fibrosis is the result of defective repair processes often seen after chronic injury and/or inflammation in a large variety of organs and tissues, such as the kidney, heart, liver, lung and skin
Relatively little is known about the direct effects of IL1b on fibroblasts, and even less is known whether IL1b influences the pro-fibrotic effect of TGFb1 towards fibroblasts
We have investigated the direct role of IL1b on dermal and lung fibroblasts, in the presence or absence of TGFb1, and found that IL1b alone did not contribute to the formation of myofibroblasts, and that IL1b on the contrary is able to attenuate or even reverse the pro-fibrotic effects of TGFb1
Summary
Fibrosis is the result of defective repair processes often seen after chronic injury and/or inflammation in a large variety of organs and tissues, such as the kidney, heart, liver, lung and skin. Lung and skin fibrosis are mediated by the IL1b [6,7,8]. It is expressed in the acute phase of inflammation, but is elevated in the later stages of inflammation and tissue repair. The consensus is that myofibroblasts are responsible for the excessive deposition of ECM in fibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
