Prostaglandin E2 inhibition of keloid fibroblast migration, contraction, and transforming growth factor (TGF)‐β1–induced collagen synthesis

Abstract

Keloid formation has been linked to aberrant fibroblast activity, exacerbated by growth factors and inflammatory mediators. Prostaglandin E2 (PGE2), synthesized from arachidonic acid by cyclooxygenases (COX) and synthases (PGES), acts as both an inflammatory mediator and fibroblast modulator. Although PGE2 has known antifibrotic effects in the lower airway, its role in dermal fibrosis in general, and keloid formation in particular, remains unclear. This study focused on: (1) the effects of PGE2 on keloid fibroblast migration, contraction, and collagen synthesis and (2) endogenous PGE2 synthesis in response interleukin-1beta. PGE2 decreased keloid fibroblast migration and contraction via an EP2/EP4-cAMP mechanism that disrupted actin cytoskeletal dynamics and reversed transforming growth factor-beta1-induced collagen I and III synthesis. Impaired fibroblast PGE2 production has been linked to lower airway fibrosis and recently to keloid formation. Here, we showed that interleukin-1beta stimulation leads to nuclear factor-kappaB translocation to the nucleus, resulting in up-regulation of COX-2 and microsomal PGE2 synthase 1. Up-regulation of COX-2 in, and secretion of PGE2 by keloid fibroblasts are diminished compared with their normal fibroblast counterparts. We suggest that the antifibrotic effects of PGE2 during keloid formation are potentially diminished due to aberrant paracrine fibroblast signaling. Exogenous PGE2 may supplement decreased endogenous levels and inhibit keloid formation or progression.

Upregulation of proinflammatory genes in skin lesions may be the cause of keloid formation (Review)

“…It was previously proposed that keloid formation may result from inflammation arising from the secretion of proinflammatory mediators and the abnormal response to other inflammatory signals mediated by keloid fibroblasts (12). In accordance with this hypothesis, Chen et al (24) and Messadi et al (25) demonstrated that ~15% of the genes, the most important being proinflammatory factors, such as IL-1α, IL-1β, IL-6 and TNF-α, were upregulated in keloid fibroblasts.…”

“…By using gene chip technology, Chen et al (24) and Messadi et al (19) discovered that ~15% of genes in keloid fibroblasts, the most important being proinflammatory factors, were upregulated, suggesting that keloid fibroblasts are crucial in the occurrence of chronic inflammation. It was proposed that keloid formation may be caused by inflammation arising from the abnormal secretion of proinflammatory mediators and irregular response to other inflammatory signals mediated by keloid fibroblasts (12). It was also proven that, as a special form of wound healing, keloids exhibit characteristics similar to the long-lasting inflammatory responses, immune abnormalities and invasive growth characteristics of tumors (31,32).…”

“…Previous clinical, histopathological and molecular studies revealed the presence of chronic inflammation in keloids, suggesting that trauma or local inflammation may lead to keloid formation (9)(10)(11)(12). Therefore, we hypothesized that the proinflammatory genes in the keloid lesion area are stimulated by the inflammatory response in the microenvironment, leading to the formation of keloids.…”

So-called ^|^ldquo;Denture Fibroma^|^rdquo;: A Histopathological and Immunohistochemical Study

“…Therefore, it was suggested that inflammatory granulation tissue formation was caused by fibroblastic stimulation accelerated by COX-2 26) in ill-fitting denture. Regarding the relevance of COX-2 and fibrosis, decreased COX-2 activation and PGE2 levels during tissue repair were associated with increased fibrosis and poor repair outcomes in the lung 27,28) . From the above results, in matured fibrous type, the transition from inflammatory to fibrous tissue type was thought to have been caused by decreased COX-2 expression.…”

Applied Basic Science of the Auricular Cartilage

“…Histopathologically, keloid is included in the spectrum of fibroproliferative disorders and commonly affects the ears, it has been suggested that keloid scarring is caused by an inability to stop the wound healing process and abnormal response to inflammation by fibroblasts [63,64]. Scar is densely populated by inflammatory cells, which release fibrogenic factors such as transforming growth factor (TGF)-β1 and -β2.…”