Abstract
Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS), a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO) caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R) related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / physiology
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Calgranulin A / genetics
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Calgranulin A / metabolism
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Calgranulin B / genetics
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Calgranulin B / metabolism
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Cells, Cultured
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Dermatitis / immunology
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Dermatitis / metabolism*
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Dermatitis / pathology
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Gene Expression
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Hyperplasia / immunology
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Hyperplasia / metabolism
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Hyperplasia / pathology
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Interleukins / genetics
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Interleukins / metabolism
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Interleukins / physiology*
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Keratinocytes
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Receptors, Interleukin / metabolism*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism*
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Suppressor of Cytokine Signaling Proteins / physiology
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beta-Defensins / genetics
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beta-Defensins / metabolism
Substances
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Calgranulin A
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Calgranulin B
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Interleukins
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Receptors, Interleukin
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S100A9 protein, mouse
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S100a8 protein, mouse
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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beta-Defensins
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interleukin-20 receptor