Abstract
Wound healing and the management of chronic wounds represent a significant burden on the NHS. Members of the suppressor of cytokine signalling (SOCS) family have been implicated in the regulation of a range of cellular processes. The current study aims to explore the importance of SOCS-3 and SOCS-4 in regulating cellular traits associated with wound healing. SOCS-3 over-expression and SOCS-4 knockdown mutant lines were generated and verified using q-PCR and western blotting in human keratinocytes (HaCaT) and endothelial cells (HECV). Over-expression of SOCS-3 resulted in a significantly reduced proliferative rate in HaCaT keratinocytes and also enhanced the tubule formation capacity of HECV cells. SOCS-4 knockdown significantly reduced HaCaT migration and HECV cell tubule formation. Suppression of SOCS-4 influenced the responsiveness of HaCaT and HECV cells to EGF and TGFβ and resulted in a dysregulation of phospho-protein expression in HaCaT cells. SOCS-3 and SOCS-4 appear to play regulatory roles in a number of keratinocyte and endothelial cellular traits associated with the wound healing process and may also be able to regulate the responsiveness of these cells to EGF and TGFβ. This implies a potential regulatory role in the wound healing process and, thus highlights their potential as novel therapies.
Highlights
Chronic wounds are defined as wounds that fail to follow the orderly and timely reparative process seen in normal healing, which in turn disrupts the anatomic and functional integrity of the wound site[1]
Our results indicated that following suppression of Suppressor of cytokine signalling (SOCS)-4 in HaCaT cells the ten most significantly enhanced phosphorylation events were Met Y1003, platelet derived growth factor receptor alpha (PDGFRα) Y754, SH2 domain-containing transforming protein 1 (ShC1) Y239/Y240, double-stranded RNA-dependent protein-serine kinase (PKR1) T446, cyclin-dependent kinase 1/2 (CDK1/2) Y15, NFKB inhibitor epsilon (IkBe) S22, histone deacetylase 5 (HDAC5) S498, Forkhead box protein O1 (FKHR) S256, c- Jun N-terminal kinase 1/2/3 (JNK 1/2/3) T183/Y185 and cyclin-dependent protein-serine kinase 4 (CDK4) T172 (Fig. 8a)
During the proliferation and re-epithelialisation phase, the proliferative behaviour and the migratory action of epithelial cells partially determine wound healing speed, the epithelial cell is an essential cell type involved in the wound healing process
Summary
Chronic wounds are defined as wounds that fail to follow the orderly and timely reparative process seen in normal healing, which in turn disrupts the anatomic and functional integrity of the wound site[1]. Several members of the SOCS family have been extensively studied in different areas of research and have been discovered to be able to regulate a wide variety of cytokines and growth factors which play key roles in the wound healing process[12]. In addition to disrupting acute wound healing, mice over-expressing SOCS-3 exhibit a prolonged inflammation phenotype that resembled characteristics of chronic wounds[15]. Taken together, these studies demonstrate the important regulatory role of SOCS-3 in the wound healing process. Since inflammation and hypoxia are involved in wound healing, SOCS-4 may have a regulatory role within the wound healing process
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