Abstract
Objectives: Inflammation is an underlying mechanism behind fibrotic processes and differentiation of cells into myofibroblasts. Presented study therefore provides new data on activation of autoimmune and inflammatory immune response genes that accompany activation of p38 and cell differentiation in primary cells derived from Dupuytren's disease (DD) patients.Methods: Primary non-Dupuytren's disease cells (ND) were isolated from macroscopically unaffected palmar fascia adjacent to diseased tissue obtained from patients diagnosed with the last stage of DD and cultured in vitro. Gene expression, collagen gel contraction assay and analysis of secreted proteins were performed in ND cells treated with TGF-β1 and/or inhibitor of p38 phosphorylation.Results: During differentiation of ND fibroblasts, increased expression of immune response genes PAI-1, TIMP-1, CCL11, and IL-6 was found. These changes were accompanied by increased cell contractility and activation of p38 and its target kinase MK2. Inhibition of p38 phosphorylation reversed these processes in vitro.Conclusions: TGF-β1 induced p38 phosphorylation in ND cells grown from macroscopically unaffected palmar fascia adjacent to diseased tissue from DD patients. This was accompanied by activation of the cytokine genes CCL-11 and IL-6 and secretion of extracellular matrix regulatory proteins PAI-1 and TIMP-1. A combined approach directed toward inflammation and p38 MAPK-mediated processes in DD might be considered for improving management of DD patients and prevention of recurrence.
Highlights
Fibrotic and fibroproliferative disorders may affect all tissues causing loss of tissue structure and function (Wynn, 2008)
We previously reported on the involvement of p38 MAPK signaling pathway in primary cells grown from Dupuytren’s disease (DD) patients (Ratkaj et al, 2012)
We studied p38 MAPK downstream target, MK2 kinase, during differentiation of primary ND cells into myofibroblasts
Summary
Fibrotic and fibroproliferative disorders may affect all tissues causing loss of tissue structure and function (Wynn, 2008) This process involves differentiation of cells into myofibroblasts accompanied by extracellular matrix deposition. Infiltrating immune cells in DD excrete large amount of different cytokines, chemokines and growth factors, especially TGF-β1 (Baird et al, 1993), cytokine that induces typical phenotypic changes and inflammation (Parsonage et al, 2005; Lupher and Gallatin, 2006). Under such conditions, cells may acquire myofibroblast phenotype. We analyzed the expression of pro-inflammatory cytokine genes in primary cells grown from DD patients and found that TGF-β1 induced p38 phosphorylation in ND cells grown from macroscopically unaffected palmar fascia adjacent to diseased tissue from DD patients is accompanied by activation of the cytokine genes CCL-11 and IL-6 and secretion of extracellular matrix regulatory proteins PAI-1 and TIMP-1, which casts new light on pathogenesis of DD
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