title: The suppressor of cytokine signaling-3 is upregulated in impaired skin repair: implications for keratinocyte proliferation.
abstract: In this study, we determined regulation and function of the suppressor of cytokine signaling (SOCS)-3 in acute and impaired murine skin repair. Upon skin injury, SOCS-3 was induced and expressed during the inflammatory phase of repair. SOCS-3 protein expression was localized in a subset of non-proliferating keratinocytes within the developing wound margin epithelia. Growth factors (EGF, transforming growth factor-alpha), nitric oxide (NO), and pro-inflammatory cytokines were inducers of SOCS-3 mRNA and protein expression in cultured human (HaCaT) and primary murine keratinocytes. Stable overexpression of SOCS-3 in HaCaT keratinocytes interfered with cytokine-induced signal transducers and activators of transcription-3 phosphorylation and inhibited serum-stimulated proliferation of the cells. Moreover, overexpression of SOCS-3 led to final differentiation of keratinocytes, which was comparable to the Ca(2+)-induced differentiation process in the cells. Finally, we determined SOCS-3 expression in two models of impaired skin repair: NO-deficient and diabetic wound healing. In line with observations from normal repair and SOCS-3 overexpression experiments, reduced keratinocyte proliferation within atrophied neo-epithelia in both models of impaired healing was associated with a marked increase in SOCS-3-expressing wound keratinocytes. In summary, this study suggests a potential novel function of SOCS-3 in regulating keratinocyte proliferation and differentiation in vitro and during skin repair in vivo.
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.forename: Andreas
authors.initials: A
authors.lastname: Linke
authors.forename: Elke
authors.initials: E
authors.lastname: Müller
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009569:Nitric Oxide / Q000494:pharmacology; D012038:Regeneration; D012867:Skin / Q000293:injuries* / Q000378:metabolism; D012879:Skin Physiological Phenomena; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D019394:Ki-67 Antigen; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016211:Transforming Growth Factor alpha; D009569:Nitric Oxide; D004815:Epidermal Growth Factor