Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts

Abstract

In skin, fibroblasts of the connective tissue play a decisive role in epidermal homeostasis and repair by contributing to the regulation of keratinocyte proliferation and differentiation. The AP-1 transcription factor subunit JUN plays a crucial role in this mesenchymal-epithelial interplay by regulating the expression of two critical paracrine-acting cytokines, keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We have performed gene expression profiling of wild-type and Jun–/– mouse embryonic fibroblasts to identify additional players involved in this complex network, and have found pleiotrophin (PTN) and the stromal cell-derived factor 1 (SDF-1) as novel JUN-regulated factors. Both cytokines are expressed by dermal fibroblasts in vivo, as shown by semi-quantitative RT-PCR and in situ hybridization on murine skin sections. Using a heterologous feeder layer co-culture system, we demonstrated that PTN and SDF-1 exert a mitogenic effect on primary human keratinocytes. Moreover, SDF-1-induced keratinocyte proliferation could be specifically inhibited by neutralizing antibodies against SDF-1 or its receptor, CXCR4. Consistent with its role in promoting keratinocyte growth, PTN was upregulated during cutaneous wound healing in vivo. Interestingly, co-cultivation with keratinocytes stimulated PTN expression but repressed SDF-1 production in fibroblasts, demonstrating the complexity of the paracrine regulatory cytokine networks that control skin homeostasis and regeneration.

Anticancer effects of amooranin in human colon carcinoma cell line in vitro and in nude mice xenografts

“…Since JUN gene is involved in cell proliferation and differentiation, AMR-induced down-regulation may be advantageous for inhibition of tumor growth. 45 In short, microarray data showed that the antitumor effect of AMR is through its regulatory effects on functional genomics targeting the apoptotic process. The house keeping gene glyceraldehyde-3-phosphate dehydrogenase (G3PDH) gene was used as control.…”

Fibroblast heterogeneity: implications for human disease

“…IL-1 has been identified as an inducing factor in these coculture experiments (96,97). Conversely, factors secreted by fibroblasts influence the growth and differentiation of keratinocytes, indicating reciprocal cellcell interaction (98). Additionally, ECM context has an important impact on fibroblast cellular identity.…”

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…97 Several other ligand-receptor combinations appear to positively influence keratinocyte migration and proliferation in vitro. 98,99 In vivo studies in CXCL11…”