Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation through Activation of EGFR Signalling in Fibroblasts

Abstract

The potential of recombinant human prolidase (rhPEPD) to induce wound healing in an experimental model of IL-1β-induced inflammation in human fibroblasts was studied. It was found that rhPEPD significantly increased cell proliferation and viability, as well as the expression of the epidermal growth factor receptor (EGFR) and downstream signaling proteins, such as phosphorylated PI3K, AKT, and mTOR, in the studied model. Moreover, rhPEPD upregulated the expression of the β1 integrin receptor and its downstream signaling proteins, such as p-FAK, Grb2 and p-ERK 1/2. The inhibition of EGFR signaling by gefitinib abolished rhPEPD-dependent functions in an experimental model of inflammation. Subsequent studies showed that rhPEPD augmented collagen biosynthesis in IL-1β-treated fibroblasts as well as in a wound healing model (wound closure/scratch test). Although IL-1β treatment of fibroblasts increased cell migration, rhPEPD significantly enhanced this process. This effect was accompanied by an increase in the activity of MMP-2 and MMP-9, suggesting extracellular matrix (ECM) remodeling during the inflammatory process. The data suggest that rhPEPD may play an important role in EGFR-dependent cell growth in an experimental model of inflammation in human fibroblasts, and this knowledge may be useful for further approaches to the treatment of abnormalities of wound healing and other skin diseases.

Multi-target mechanism of polyherbal extract to treat diabetic foot ulcer based on network pharmacology and molecular docking

“…This tyrosine kinase enzyme phosphorylates specific intracellular substrates, initiating signaling pathways that ultimately result in cellular proliferation (43). According to previous studies, EGFR promotes cell proliferation, angiogenesis, and invasion (44,45). The motility of keratinocyte stem cells, driven by the EGFR-collagen type XVII α1 (COL17A1) axis, plays a crucial role in epidermal regeneration, suggesting a promising therapeutic strategy for addressing defective skin regeneration (46).…”

KLF6 activates Sp1-mediated prolidase transcription during TGF-β1 signaling

“…A number of reports also show increased prolidase mRNA levels and higher enzymatic activity in wound fluid and scar tissues ( 16 , 17 ). Furthermore, a recent study showed that recombinant human prolidase induces cell growth, proliferation, migration, and collagen biosynthesis in human fibroblasts ( 18 ). However, the mechanisms and pathways that regulate prolidase expression are poorly understood.…”