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Merck
  • Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis.

Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis.

JID innovations : skin science from molecules to population health (2022-02-12)
Hanna Niehues, Gijs Rikken, Ivonne M J J van Vlijmen-Willems, Diana Rodijk-Olthuis, Piet E J van Erp, Patrick L J M Zeeuwen, Joost Schalkwijk, Ellen H van den Bogaard
摘要

Psoriasis and atopic dermatitis are chronic inflammatory skin diseases characterized by keratinocyte (KC) hyperproliferation and epidermal acanthosis (hyperplasia). The milieu of disease-associated cytokines and soluble factors is considered a mitogenic factor; however, pinpointing the exact mitogens in this complex microenvironment is challenging. We employed organotypic human epidermal equivalents, faithfully mimicking native epidermal proliferation and stratification, to evaluate the proliferative effects of a broad panel of (literature-based) potential mitogens. The KC GF molecule, the T-helper 2 cytokines IL-4 and IL-13, and the psoriasis-associated cytokine IL-17A caused acanthosis by hyperplasia through a doubling in the number of proliferating KCs. In contrast, IFN-γ lowered proliferation, whereas IL-6, IL-20, IL-22, and oncostatin M induced acanthosis not by hyperproliferation but by hypertrophy. The T-helper 2‒cytokine‒mediated hyperproliferation was Jak/signal transducer and activator of transcription 3 dependent, whereas IL-17A and KC GF induced MAPK/extracellular signal‒regulated kinase kinase/extracellular signal‒regulated kinase‒dependent proliferation. This discovery that key regulators in atopic dermatitis and psoriasis are direct KC mitogens not only adds evidence to their crucial role in the pathophysiological processes but also highlights an additional therapeutic pillar for the mode of action of targeting biologicals (e.g., dupilumab) or small-molecule drugs (e.g., tofacitinib) by the normalization of KC turnover within the epidermal compartment.

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Sigma-Aldrich
表皮生长因子 来源于鼠颔下腺, EGF, suitable for cell culture
Sigma-Aldrich
内皮素1, ≥97% (HPLC), powder
Sigma-Aldrich
U0126 钛酸乙酯 单乙醇盐, ≥98% (HPLC), powder
Sigma-Aldrich
角质细胞生长因子 人, KGF, recombinant, expressed in E. coli, powder, suitable for cell culture
Sigma-Aldrich
p38 MAP 激酶抑制剂 IV, ≥98% (HPLC)