SMOC1 and IL-4 and IL-13 Cytokines Interfere with Ca Mobilization in Primary Human Keratinocytes.

Immunoregulatory effects of IL-4 and IL-13 and alterations of keratinocyte (KC) differentiation are important factors in the pathogenesis of atopic dermatitis. This study investigated the role of IL-4 and IL-13 in KC responses to changes in extracellular calcium (Ca) and analyzed differentiation signals elicited via a Ca sensor, SMOC1. Real-time dynamics of transmembrane Ca influx were assessed in live KCs by flow cytometry and microscopy. Exposure of KCs to a high Ca environment (1.3 mM) triggered a rapid intracellular Ca influx, whereas IL-4- and IL-13-treated cells exhibited a significant decrease in the peak amplitude of Ca influx (P < 0.01). IL-17A and IL-22 did not elicit such responses. Evaluation of intracellular Ca dynamics by microscopy confirmed these observations and revealed heterogeneity of individual KC responses. IL-4 and IL-13 significantly inhibited the expression of Ca-binding protein SMOC1 (P < 0.001). Inhibition of epidermal differentiation markers were also observed in SMOC1 small interfering RNA-transfected KCs. Concurrently, the deletion of SMOC1 increased the amplitude of Ca peak response (P < 0.05). In conclusion, our results provide innovative data that IL-4 and IL-13 regulate KC sensitivity to microenvironmental Ca changes and inhibit Ca-induced KC differentiation signals. SMOC1 inhibition by IL-4 and IL-13 alters Ca transport in KCs and inhibits differentiation, suggesting a new target for treatment of atopic dermatitis.