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

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.

Vitreal Cytokine Profile Differences Between Eyes With Epiretinal Membranes or Macular Holes

“…The cytokine profiles in our study are commensurate with an activation of fibrotic and inflammatory processes, which are associated with elevated levels of IL-6, IL-4, IL-1b, TNF-a, IL-10, IL-2, and INF-c (among others). 2,[26][27][28] In our study, five of the six chemokines and cytokines with the largest intergroup differences (CCL27, CCL26, CXCL6, INF-c, and CXCL11) are proinflammatory and play a major role in immunomodulation and inflammation, indicating a central role of inflammatory mechanisms in epiretinal membrane formation. Additionally, IL-10 was initially understood as a TH2 cytokine with regulatory properties in inflammatory processes, but meanwhile it was revealed that lymphocytes, macrophages, dendritic, natural killer, and mast cells also express IL-10.…”

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

“…Myofibroblasts are responsible for the synthesis of large amounts of ECM 1, 2, 3, 4, 28. Here, we show that ACHP is able to completely abrogate the TGFβ1‐induced differentiation of both dermal and lung fibroblasts into myofibroblasts, as revealed by the inhibition of the formation of the stress fibre components αSMA and SM22α.…”

Interleukin-1β Promotes Epithelial-Derived Alveolar Elastogenesis via αvβ6 Integrin-Dependent TGF-β Activation

“…Regarding the performance of -1 in promoting elastin expression, con licting data regarding the inductive effects of -1 exist depending on different cell type and speci icity. ne study demonstrated the absence of an effect by -1 on elastin expression in lung ibroblasts [16,39], whereas the indings of another study were suggestive of the elastogenic effects of -1 in lung ibroblasts [40]. n the alveolar epithelial cell monolayers, -1 activated TGF-1 via RhoA v 6 integrin-dependent mechanisms [33,41].…”

“…The conditional expression of -1 causes severe pulmonary in lammation, alveolar hypoplasia, and progressive lung ibrosis, whereas the in vivo bloc age or depletion of -1 alleviates in lammation and ibrosis and ultimately prevents murine bronchopulmonary dysplasia [14,15]. Regarding the direct effects of -1 on the regulation of extracellular matrix (ECM) expression and composition, con licting data exist regarding the contributions of -1 to the development of myo ibroblasts, which are critical for alveolar formation [16][17][18]. Additionally, -1 induces myo ibroblast formation and elastogenesis via both an epithelial-mesenchymal transition (EMT) [19] and an endothelial-mesenchymal transition (EndoMT) [20,21].…”