Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines

Ayako Uto-Konomi, Kosuke Miyauchi, Naoko Ozaki, Yasutaka Motomura, Yoshie Suzuki, Akihiko Yoshimura, Shinobu Suzuki, Daniel Cua, Masato Kubo

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Article numbere40343
JournalPLoS One
Volume7
Issue number7
DOIs
Publication statusPublished - 2012 Jul 5

Fingerprint

keratinocytes
interleukins
Keratinocytes
Skin
cytokines
inflammation
Cytokines
Inflammation
receptors
interleukin-6
Interleukin-6
hyperplasia
Hyperplasia
homeostasis
Homeostasis
Genes
Feedback
gene deletion
Gene Deletion
Immunoglobulin E

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines. / Uto-Konomi, Ayako; Miyauchi, Kosuke; Ozaki, Naoko; Motomura, Yasutaka; Suzuki, Yoshie; Yoshimura, Akihiko; Suzuki, Shinobu; Cua, Daniel; Kubo, Masato.

In: PLoS One, Vol. 7, No. 7, e40343, 05.07.2012.

Research output: Contribution to journalArticle

Uto-Konomi, Ayako ; Miyauchi, Kosuke ; Ozaki, Naoko ; Motomura, Yasutaka ; Suzuki, Yoshie ; Yoshimura, Akihiko ; Suzuki, Shinobu ; Cua, Daniel ; Kubo, Masato. / Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines. In: PLoS One. 2012 ; Vol. 7, No. 7.
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