title: RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells.
abstract: AGEs accumulation in the skin affects extracellular matrix (ECM) turnover and triggers diabetes associated skin conditions and accelerated skin aging. The receptor of AGEs (RAGE) has an essential contribution to cellular dysfunction driven by chronic inflammatory responses while TGF-β1 is critical in both dermal homeostasis and inflammation. We investigated the contribution of RAGE and TGF-β1 to the modulation of inflammatory response and ECM turnover in AGEs milieu, using a normal fibroblast cell line. RAGE, TGF-β1, collagen I and III gene and protein expression were upregulated after exposure to AGEs-BSA, and MMP-2 was activated. AGEs-RAGE was pivotal in NF-κB dependent collagen I expression and joined with TGF-β1 to stimulate collagen III expression, probably via ERK1/2 signaling. AGEs-RAGE axis induced upregulation of TGF-β1, TNF-α and IL-8 cytokines. TNF-α and IL-8 were subjected to TGF-β1 negative regulation. RAGE's proinflammatory signaling also antagonized AGEs-TGF-β1 induced fibroblast contraction, suggesting the existence of an inhibitory cross-talk mechanism between TGF-β1 and RAGE signaling. RAGE and TGF-β1 stimulated anti-inflammatory cytokines IL-2 and IL-4 expression. GM-CSF and IL-6 expression appeared to be dependent only on TGF-β1 signaling. Our data also indicated that IFN-γ upregulated in AGEs-BSA milieu in a RAGE and TGF-β1 independent mechanism. Our findings raise the possibility that RAGE and TGF-β1 are both involved in fibrosis development in a complex cross-talk mechanism, while also acting on their own individual targets. This study contributes to the understanding of impaired wound healing associated with diabetes complications.
authors.affiliation: Department of Preclinical Sciences, University of Agronomical Sciences and Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania.
authors.forename: Andreea Iren
authors.initials: AI
authors.lastname: Serban
authors.affiliation: Department of Preclinical Sciences, University of Agronomical Sciences and Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania.
authors.forename: Loredana
authors.initials: L
authors.lastname: Stanca
authors.affiliation: Department of Preclinical Sciences, University of Agronomical Sciences and Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania.|Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095, Bucharest, Romania.
authors.forename: Ovidiu Ionut
authors.initials: OI
authors.lastname: Geicu
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, 264 McElroy Hall, Stillwater, Oklahoma, 74078, United States of America.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Munteanu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095, Bucharest, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Dinischiotu
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007378:Interleukins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D017127:Glycation End Products, Advanced; D007378:Interleukins; D008565:Membrane Proteins; D000067759:Receptor for Advanced Glycation End Products; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen