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.