Progranulin overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway contributes to the resistance of dermal fibroblasts to the anti-fibrotic effect of tumor necrosis factor-α in localized scleroderma

Background: Dermal fibroblasts derived from patients with systemic sclerosis (SSc) overproduce progranulin (PGRN), an endogenous antagonist of tumor necrosis factor (TNF) receptors, due to the deficiency of transcription factor Flil. Flil expression is also decreased in dermal fibroblasts derived from patients with localized scleroderma (LSc). Objective: To investigate the expression levels of PGRN and its contribution to the induction of pro-fibrotic phenotype in LSc dermal fibroblasts. Methods: PGRN expression levels were determined by immunohistochemistry and quantitative reverse transcription PCR in the skin of human subjects. The role of PGRN in fibroblast activation was examined with gene silencing technique. The involvement of c-Abl/protein kinase C (PKC)-delta/Fli1 pathway in the regulation of PGRN expression was investigated by immunoblotting. Results: The expression levels of PGRN and TNF-alpha were elevated in LSc skin lesions compared with healthy control skin. LSc dermal fibroblasts were less responsive to the anti-fibrotic effect of TNF-alpha than normal dermal fibroblasts. Importantly, gene silencing of PGRN reversed the response to TNF-alpha in LSc dermal fibroblasts. Similar to SSc dermal fibroblasts, the inhibition of c-Abl/PMC-delta/Fli1 pathway by gene silencing of ABU or PRKCD significantly suppressed PGRN expression in LSc dermal fibroblasts. Conclusion: PGRN overproduction due to constitutively activated c-Abl/PKC-delta/Fli1 pathway may contribute to the resistance of LSc dermal fibroblasts to the anti-fibrotic effect of TNF-alpha, which may be involved in maintaining their pro-fibrotic phenotype under the pro-inflammatory condition, as is the case with SSc. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.