TNFα shedding and epidermal inflammation are controlled by Jun proteins

J Guinea-Viniegra, R Zenz, H Scheuch… - Genes & …, 2009 - genesdev.cshlp.org
J Guinea-Viniegra, R Zenz, H Scheuch, D Hnisz, M Holcmann, L Bakiri, HB Schonthaler…
Genes & development, 2009genesdev.cshlp.org
Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like
inflammatory skin disease. Increased levels of the proinflammatory cytokine TNFα play a
major role in this phenotype. Here we define the underlying molecular mechanism using
genetic mouse models. We show that Jun proteins control TNFα shedding in the epidermis
by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an
inhibitor of the TNFα-converting enzyme (TACE). TIMP-3 is down-regulated and TACE …
Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like inflammatory skin disease. Increased levels of the proinflammatory cytokine TNFα play a major role in this phenotype. Here we define the underlying molecular mechanism using genetic mouse models. We show that Jun proteins control TNFα shedding in the epidermis by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an inhibitor of the TNFα-converting enzyme (TACE). TIMP-3 is down-regulated and TACE activity is specifically increased, leading to massive, cell-autonomous TNFα shedding upon loss of both JunB and c-Jun. Consequently, a prominent TNFα-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 TNFα 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 TNFα levels.
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