Regulation of epithelial-mesenchymal IL-1 signaling by PPARbeta/delta is essential for skin homeostasis and wound healing.
Skin morphogenesis, maintenance, and healing after wounding require complex epithelial-mesenchymal interactions. In this study, we show that for skin homeostasis, interleukin-1 (IL-1) produced by keratinocytes activates peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARbeta/delta stimulates production of the secreted IL-1 receptor antagonist, which leads to an autocrine decrease in IL-1 signaling pathways and consequently decreases production of secreted mitogenic factors by the fibroblasts. This fibroblast PPARbeta/delta regulation of the IL-1 signaling is required for proper wound healing and can regulate tumor as well as normal human keratinocyte cell proliferation. Together, these findings provide evidence for a novel homeostatic control of keratinocyte proliferation and differentiation mediated via PPARbeta/delta regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARbeta/delta, other epithelial-mesenchymal interactions may also be regulated in a similar manner.
Chong
Han Chung
HC
School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Tan
Ming Jie
MJ
Philippe
Virginie
V
Tan
Siew Hwey
SH
Tan
Chek Kun
CK
Ku
Chee Wai
CW
Goh
Yan Yih
YY
Wahli
Walter
W
Michalik
Liliane
L
Tan
Nguan Soon
NS
D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D047494:PPAR delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D012867:Skin / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014945:Wound Healing; D000099151:MAP Kinase Kinase Kinase 7
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D047494:PPAR delta; D048068:PPAR-beta; D018808:Transcription Factor AP-1; D000099151:MAP Kinase Kinase Kinase 7