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Abstract
Wound healing is a process of stimulating cell growth and proliferation to achieve the result of repair. This process is controlled by cytokines and growth factors which regulates the speed and efficiency of repair. Cytokines such as interleukin 1 beta (IL-1beta) and tumour necrosis factor alpha (TNF-alpha) regulates repair by inducing effects on inflammatory cells and control of growth factor expression. One down-stream factor which is regulated by cytokines is platelet-derived growth factor receptor alpha (PDGF-R-alpha). This receptor is important in the proliferation of fibroblasts and smooth muscle cells, important mediators in the process of wound healing.
In this thesis, we discovered that following injury there is an induction in the expression of pro-inflammatory cytokines IL-1beta and TNF-alpha. This induction was seen after 24 and 48h exposure respectively. The effect of IL-1beta was seen to cause an increase in the proliferation of fibroblasts, whereas TNF-alpha had an inhibitory effect.
The effect of IL-1beta was determined to be mediated through transcriptional activation of PDGF-R-alpha. Following IL-1beta release, there is the translocation and activation of Nuclear Factor kappa B (NF-kappaB) and Activating Transcription Factor 4 (ATF-4). These cooperatively interact on the promoter region of PDGF-R-alpha at the -531/-521 (NF-kappaB) and -259/-254 (ATF-4) positions and remove the presence of Histone deacetylases (HDAC), hence activating PDGF-R-alpha.
On the other hand, TNF-alpha which showed an inhibitory effect on fibroblast proliferation decreased the expression of PDGF-R-alpha. This was achieved through activation of a transcription complex which contains the factors c-Fos, Interferon Regulatory Factor 1 (IRF-1) and Yin Yang 1 (YY-1). This complex recruits HDAC onto the promoter suppressing the expression of PDGF-R-alpha and its down-stream effects on proliferation.
The opposing nature of pro-inflammatory cytokine mediated events suggests that these act as a natural balance in the control of wound healing efficacy. The elucidation of the pathways controlling wound healing, in this case the control of PDGF-R-alpha, will provide therapeutic targets to improve regeneration of skin and organs following injury.