TLR2/1 and sphingosine 1-phosphate modulate inflammation, myofibroblast differentiation and cell migration in fibroblasts.
Dermal fibroblasts are important regulators of inflammatory and immune responses in the skin. The aim of the present study was to elucidate the interaction between two key players in inflammation, Toll-like receptors (TLRs) and sphingosine 1-phosphate (S1P), in normal human fibroblasts in the context of inflammation, fibrosis and cell migration. We demonstrate that TLR2 ligation strongly enhances the production of the pro-inflammatory cytokines IL-6 and IL-8. S1P significantly induces pro-inflammatory cytokines time- and concentration-dependently via S1P receptor (S1PR)2 and S1PR3. The TLR2/1 agonist Pam3CSK4 and S1P (>1μM) or TGF-β markedly upregulate IL-6 and IL-8 secretion. Pam3CSK4 and S1P alone promote myofibroblast differentiation as assessed by significant increases of α-smooth muscle actin and collagen I expression. Importantly, costimulation with S1P (>1μM) induces differentiation into myofibroblasts. In contrast, Pam3CSK4 and low S1P concentrations (<1μM) accelerate cell migration. These results suggest that TLR2/1 signaling and S1P cooperate in pro-inflammatory cytokine production and myofibroblast differentiation and promote cell migration of skin fibroblasts in a S1P-concentration dependent manner. Our findings provide significant insights into how infectious stimuli or danger signals and sphingolipids contribute to dermal inflammation which may be relevant for skin tissue repair after injury or disease.
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, 14195 Berlin, Germany.
Saghi
S
Hamidi
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, 14195 Berlin, Germany.
Monika
M
Schäfer-Korting
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, 14195 Berlin, Germany. Electronic address: Guenther.Weindl@fu-berlin.de.
Günther
G
Weindl
D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism
D015850:Interleukin-6; D016209:Interleukin-8; D055666:Lipopeptides; D008246:Lysophospholipids; C508075:Pam(3)CSK(4) peptide; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; C060506:sphingosine 1-phosphate; D003094:Collagen; D013110:Sphingosine
Cytokine; Dermal fibroblast; Myofibroblast; Sphingosine-1-phosphate; Toll-like receptor