Goren Itamar, Linke Andreas, Müller Elke, Pfeilschifter Josef, Frank Stefan
Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
J Invest Dermatol. 2006 Feb;126(2):477-85. doi: 10.1038/sj.jid.5700063.
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.
在本研究中，我们确定了细胞因子信号转导抑制因子（SOCS）-3在急性和受损小鼠皮肤修复中的调控作用及功能。皮肤损伤后，SOCS-3在修复的炎症阶段被诱导并表达。SOCS-3蛋白表达定位于正在形成的伤口边缘上皮内的一部分非增殖角质形成细胞中。生长因子（表皮生长因子、转化生长因子-α）、一氧化氮（NO）和促炎细胞因子是培养的人（HaCaT）和原代小鼠角质形成细胞中SOCS-3 mRNA和蛋白表达的诱导剂。在HaCaT角质形成细胞中稳定过表达SOCS-3会干扰细胞因子诱导的信号转导子和转录激活子-3磷酸化，并抑制细胞的血清刺激增殖。此外，SOCS-3的过表达导致角质形成细胞最终分化，这与细胞中Ca(2+)诱导的分化过程相当。最后，我们在两种皮肤修复受损模型中确定了SOCS-3的表达：NO缺乏和糖尿病伤口愈合。与正常修复和SOCS-3过表达实验的观察结果一致，在两种愈合受损模型中，萎缩的新上皮内角质形成细胞增殖减少与表达SOCS-3的伤口角质形成细胞显著增加有关。总之，本研究表明SOCS-3在体外和体内皮肤修复过程中调节角质形成细胞增殖和分化方面具有潜在的新功能。
