Changes in Epidermal Cell Proliferation in Proliferative Skin Disease

Wright, Nicholas A.

doi:10.1007/978-3-642-69574-2_4

Cited by 2 publications

(1 citation statement)

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“…However, under certain circumstances, this tightly regulated process is disturbed, and basal KCs remain hyperproliferative. Besides being related to malignancies ( Frost et al., 1966 ; Wright, 1985 ), KC hyperproliferation is a classic feature of several benign skin disorders, including the chronic inflammatory skin diseases psoriasis ( Leigh et al., 1985 ; Vanscott and Ekel, 1963 ; Weinstein et al., 1985 ) and atopic dermatitis (AD) ( Sapuntsova et al., 2002 ). Although the underlying pathogenesis and pathophysiological processes are distinct, both diseases are typically characterized by epidermal thickening (acanthosis) owing to hyperplasia (increased cell numbers).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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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