Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARgamma activation.
Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne. It has also been shown to be effective in rosacea; however, the mechanism of action has not been clarified. Because inflammation is a common feature of both conditions, we investigated the effects of azelaic acid on the inflammatory response of normal human keratinocytes to ultraviolet B light, which is a photosensitizer agent in rosacea. AzA, at 20 mM, a concentration achievable following topical application of a 15% gel, suppresses ultraviolet B light-induced interleukins-1beta, -6 and tumor necrosis factor-alpha mRNA expression and protein secretion. Mechanistically, azelaic acid significantly reduced the ultraviolet B light-induced nuclear translocation of nuclear factor kB p65 subunit and the phosphorylation of the p38 mitogen and stress-activated protein kinase. Moreover, as peroxisome proliferators-activated receptor gamma, (PPARgamma) which has a crucial role in the control of inflammation, is activated by fatty acids and products of lipid peroxidation, we further investigated the effect of azelaic acid on the expression of this nuclear receptor. AzA induced peroxisome proliferators-activated receptor-gamma mRNA and its transcriptional activity. The PPARgamma antagonist GW9662 abrogated the inhibitory effects of AzA on the UVB-induced pro-inflammatory cytokines release and on the cell proliferation. Our study provides new insights into the molecular mechanisms of the activity of azelaic acid and lands additional evidences for its therapeutic effects on inflammatory skin diseases, such as rosacea.
Mastrofrancesco
Arianna
A
Laboratorio di Fisiopatologia Cutanea e Centro Integrato di Metabolomica, San Gallicano Dermatologic Institute IRCCS, Rome, Italy.
Ottaviani
Monica
M
Aspite
Nicaela
N
Cardinali
Giorgia
G
Izzo
Enzo
E
Graupe
Klaus
K
Zouboulis
Christos C
CC
Camera
Emanuela
E
Picardo
Mauro
M
D000152:Acne Vulgaris / Q000188:drug therapy*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003879:Dermatologic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003998:Dicarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D017930:Genes, Reporter; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012393:Rosacea / Q000188:drug therapy; D014158:Transcription, Genetic / Q000187:drug effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D003879:Dermatologic Agents; D003998:Dicarboxylic Acids; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C010038:azelaic acid