title: 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.
authors.affiliation: Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Masum M
authors.initials: MM
authors.lastname: Mia
authors.affiliation: Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Boersema
authors.affiliation: Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008168:Lung / Q000166:cytology*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology* / Q000187:drug effects; D015513:Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C439971:COL3A1 protein, human; D024042:Collagen Type I; D024061:Collagen Type III; D053823:Hedgehog Proteins; D053583:Interleukin-1beta; D015513:Oncogene Proteins; C508960:TGFB1 protein, human; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D000071676:Zinc Finger Protein GLI1; D020782:Matrix Metalloproteinases