Chemokine and chemokine receptor expression in keloid and normal fibroblasts

Abstract

Keloids are benign collagenous tumors that occur during dermal wound healing in genetically predisposed individuals. The lesions are characterized by over-proliferation of fibroblasts, some leukocyte infiltration, and prolonged high rates of collagen synthesis. To determine whether leukocyte chemoattractants or chemokines are participating in this disease process, immunohistochemical staining for the CXC chemokine, MGSA/GRO␣, and its receptor, CXCR2, was performed on tissue from keloids, hypertrophic scars and normal skin. Immunoreactive MGSA/GRO␣ was not observed in hypertrophic scars or normal dermis, but was present in some myofibroblasts and lymphocytes in nodular areas of the keloid samples. This staining positively correlated with the degree of inflammatory infiltrate in the lesions. Keloids, but not hypertrophic scars or normal dermis, also exhibited intensive immunoreactivity for the CXCR2 receptor in endothelial cells and inflammatory infiltrates with occasional staining of myofibroblasts. In contrast, cultured fibroblasts from either keloids or normal skin did not express detectable amounts of mRNA for MGSA/GRO or CXCR2, although interleukin-1 strongly induced MGSA/GRO mRNA in both cell types. Interleukin-1 induction of MGSA/GRO was inhibited by glucocorticoid in normal and keloid fibroblasts, and the effect was more pronounced in keloid fibroblasts. This event was not correlated with inhibition of nuclear activation of NF-B, AP-1 or Sp1, and might therefore be mediated by another mechanism such as decreased mRNA stability or transcriptional repression through the glucocorticoid response element in the MGSA/GRO promoter. Data from in vitro wounding experiments with cultured normal and keloid fibroblasts indicate that there were no significant differences in MGSA/GRO or CXCR2 receptor levels between normal and keloid fibroblasts. We also show that cultured keloid fibroblasts exhibit a delayed wound healing response. We postulate that the inflammatory component is important in development of keloid lesions and chemotactic cytokines may participate in this process. (WOUND REP REG 2000;8:371-382)

The role of Duffy antigen receptor for chemokines in keloids

“…Our results also showed that the changes of DARC in keloid fibroblasts were not related to fibroblast proliferation. However, in line with a previous study (Nirodi et al, 2011), wound closure was significantly slower in injured keloid fibroblasts than in normal fibroblasts. When DARC was interrupted, the migration of keloid fibroblasts was promoted.…”

“…In humans, CCL2 is a major factor in progressive renal fibrosis, ischemic cardiomyopathy, atherosclerosis, and pancreatitis (Tesch, 2008;Xia and Frangogiannis, 2007;Marra, 2005), which can stimulate the expression of fibroblast collagen (van Horssen et al, 2006). Moreover, the enhancement of CCL2 and CCR2 has also been reported in keloid tissues, augmenting the fibroblast proliferation (Nirodi et al, 2011). CXCL8 is another important chemokine mediating inflammation, which is assumed to be the macrophage-derived mediator of angiogenesis.…”

“…There is also increasing evidence implying the association between chemokines and keloid pathogenesis. For example, MGSA/GROα has been found to be expressed in keloids, which is associated with the inflammation within the lesions (Nirodi et al, 2011).…”

Keloid or Hypertrophic Scar

“…Keloids are fibrous overgrowths at sites of cutaneous injury that form as a result of an abnormal wound-healing process in genetically susceptible individuals 12,13 and, unlike normal scars, do not regress. 6,14,15 Keloid disease is a benign dermal fibroproliferative tumor unique to humans 6,14 -16 that never becomes malignant.…”

Aspidin PB, a novel natural anti-fibrotic compound, inhibited fibrogenesis in TGF-β1-stimulated keloid fibroblasts via PI-3K/Akt and Smad signaling pathways

“…Surgical scars are not only a cosmetic concern but they can also cause a number of side effects including pain, itching, discomfort, contracture, and other functional impairment [1,2]. Any patient may develop keloids, but dark skinned ethnicities are more susceptible to keloid formation with upwards of 15% of the population at a heightened risk [3][4][5][6][7]. However, keloids have still not a definitive therapy.…”