TNFalpha shedding and epidermal inflammation are controlled by Jun proteins.
Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like inflammatory skin disease. Increased levels of the proinflammatory cytokine TNFalpha play a major role in this phenotype. Here we define the underlying molecular mechanism using genetic mouse models. We show that Jun proteins control TNFalpha shedding in the epidermis by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an inhibitor of the TNFalpha-converting enzyme (TACE). TIMP-3 is down-regulated and TACE activity is specifically increased, leading to massive, cell-autonomous TNFalpha shedding upon loss of both JunB and c-Jun. Consequently, a prominent TNFalpha-dependent cytokine cascade is initiated in the epidermis, inducing severe skin inflammation and perinatal death of newborns from exhaustion of energy reservoirs such as glycogen and lipids. Importantly, this metabolic "cachectic" phenotype can be genetically rescued in a TNFR1-deficient background or by epidermis-specific re-expression of TIMP-3. These findings reveal that Jun proteins are essential physiological regulators of TNFalpha shedding by controlling the TIMP-3/TACE pathway. This novel mechanism describing how Jun proteins control skin inflammation offers potential targets for the treatment of skin pathologies associated with increased TNFalpha levels.
Guinea-Viniegra
Juan
J
Cancer Cell Biology Programme, Centro Nacional de Investigaciones, Oncológicas (CNIO), E-28029 Madrid, Spain.
Zenz
Rainer
R
Scheuch
Harald
H
Hnisz
Denes
D
Holcmann
Martin
M
Bakiri
Latifa
L
Schonthaler
Helia B
HB
Sibilia
Maria
M
Wagner
Erwin F
EF
D000818:Animals; D002100:Cachexia / Q000235:genetics / Q000401:mortality; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000503:physiopathology; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012871:Skin Diseases / Q000503:physiopathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D016755:Proto-Oncogene Proteins c-jun; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha