Interleukin-1β Attenuates Myofibroblast Formation and Extracellular Matrix Production in Dermal and Lung Fibroblasts Exposed to Transforming Growth Factor-β1

One of the most potent pro-fibrotic cytokines is transforming growth factor (TGF beta). TGF beta is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1 beta (IL1 beta) 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 IL1 beta, TGF beta 1, and IL1 beta in combination with TGF beta 1 on myofibroblast formation, collagen synthesis and collagen modification (including prolyl hydroxylase, lysyl hydroxylase and lysyl oxidase), and matrix metalloproteinases (MMPs). We found that IL1 beta alone has no obvious pro-fibrotic effect on fibroblasts. However, IL1 beta is able to inhibit the TGF beta 1-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 TGF beta 1. The addition of IL1 beta reduced the expression of GLI1 and thereby also indirectly inhibits myofibroblast formation. Other potentially anti-fibrotic effects of IL1 beta that were observed are the increased levels of MMP1, -2, -9 and -14 produced by fibroblasts exposed to TGF beta 1/IL1 beta in comparison with fibroblasts exposed to TGF beta 1 alone. In addition, IL1 beta decreased the TGF beta 1-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 IL1 beta. Suppression of COL1A1 by IL1 beta in the presence of TGF beta 1 is more pronounced in lung fibroblasts compared to dermal fibroblasts, whereas a higher upregulation of MMP1 is seen in dermal fibroblasts. The role of IL1 beta 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.