Peroxisome proliferator-activated receptor-alpha activation inhibits Langerhans cell function.
Epidermal Langerhans cells (LC) play a pivotal role in initiating and maintaining primary immune responses in the skin. In the present study, we asked whether peroxisome proliferator-activated receptor-alpha (PPARalpha) activation modulates LC function. Our results show that PPARalpha is expressed in immature LC and is down-regulated in mature LC suggesting that an early decrease of PPARalpha expression in LC may allow them to mature after contact with an Ag. We further show that pharmacologic PPARalpha activation inhibits LC maturation, migratory capacity, cytokine expression, and the ability to drive T cell proliferation. Moreover, PPARalpha activation inhibits NF-kappaB but not stress-activated protein kinase/JNK, p38MAPK, and ERK1/2. In conclusion, PPARalpha activation by endogenous ligands may provide a molecular signal that allows LC to remain in an immature state within the epidermis for extended periods of time despite minor environmental stimuli.
Dubrac
Sandrine
S
Department of Dermatology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. sandrine.dubrac@i-med.ac.at
Stoitzner
Patrizia
P
Pirkebner
Daniela
D
Elentner
Andreas
A
Schoonjans
Kristina
K
Auwerx
Johan
J
Saeland
Sem
S
Hengster
Paul
P
Fritsch
Peter
P
Romani
Nikolaus
N
Schmuth
Matthias
M
D000818:Animals; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D007801:Langerhans Cells / Q000737:chemistry / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047493:PPAR alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D047493:PPAR alpha; D011743:Pyrimidines; D051996:Transcription Factor RelA; C006253:pirinixic acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4