Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting various tissues. Involvement of B and T cells as well as increased cytokine levels have been associated with disease manifestation. Recently, we demonstrated that mice with epidermal loss of JunB (JunB(Deltaep)) develop a myeloproliferative syndrome (MPS) due to high levels of G-CSF which are secreted by JunB-deficient keratinocytes. In addition, we show that JunB(Deltaep) mice develop a SLE phenotype linked to increased epidermal interleukin 6 (IL-6) secretion. Intercrosses with IL-6-deficient mice could rescue the SLE phenotype. Furthermore, we show that JunB binds to the IL-6 promoter and transcriptionally suppresses IL-6. Facial skin biopsies of human SLE patients similarly revealed low JunB protein expression and high IL-6, activated Stat3, Socs-1, and Socs-3 levels within lupus lesions. Thus, keratinocyte-induced IL-6 secretion can cause SLE and systemic autoimmunity. Our results support trials to use alpha-IL-6 receptor antibody therapy for treatment of SLE.
Pflegerl
Pamina
P
Institute of Clinical Pathology, Department of Internal Medicine III, Medical University of Vienna, Währingergürtel 18-20, A-1090 Vienna, Austria.
Vesely
Paul
P
Hantusch
Brigitte
B
Schlederer
Michaela
M
Zenz
Rainer
R
Janig
Elke
E
Steiner
Günter
G
Meixner
Arabella
A
Petzelbauer
Peter
P
Wolf
Peter
P
Soleiman
Afschin
A
Egger
Gerda
G
Moriggl
Richard
R
Kishimoto
Tadamitsu
T
Wagner
Erwin F
EF
Kenner
Lukas
L
D000818:Animals; D047369:Chromatin Immunoprecipitation; D003433:Crosses, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000378:metabolism*; D019085:Fluorescent Antibody Technique, Direct; D005786:Gene Expression Regulation / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008156:Luciferases; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency* / Q000378:metabolism
D015850:Interleukin-6; D016755:Proto-Oncogene Proteins c-jun; D016179:Granulocyte Colony-Stimulating Factor; D008156:Luciferases