Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts.
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.
Florin
Lore
L
Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Maas-Szabowski
Nicole
N
Werner
Sabine
S
Szabowski
Axel
A
Angel
Peter
P
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008858:Microscopy, Phase-Contrast; D020411:Oligonucleotide Array Sequence Analysis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D014945:Wound Healing
C515255:CXCL12 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D018076:DNA, Complementary; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D051523:Fibroblast Growth Factor 7; C066845:pleiotrophin; D005346:Fibroblast Growth Factors; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor