Interleukin-1b Attenuates Myofibroblast Formation and Extracellular Matrix Production in Dermal and Lung Fibroblasts Exposed to Transforming Growth Factor-b1

One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFb). TGFb is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1b (IL1b) 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 IL1b, TGFb1, and IL1b in combination with TGFb1 on myofibroblast formation, collagen synthesis and collagen modification (including prolyl hydroxylase, lysyl hydroxylase and lysyl oxidase), and matrix metalloproteinases (MMPs). We found that IL1b alone has no obvious pro-fibrotic effect on fibroblasts. However, IL1b is able to inhibit the TGFb1-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 TGFb1. The addition of IL1b reduced the expression of GLI1 and thereby also indirectly inhibits myofibroblast formation. Other potentially anti-fibrotic effects of IL1b that were observed are the increased levels of MMP1, 22, 29 and 214 produced by fibroblasts exposed to TGFb1/IL1b in comparison with fibroblasts exposed to TGFb1 alone. In addition, IL1b decreased the TGFb1-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 IL1b. Suppression of COL1A1 by IL1b in the presence of TGFb1 is more pronounced in lung fibroblasts compared to derma