SPARC Related Modular Calcium Binding Protein 1 and IL-4/IL-13 Cytokines Interfere with Ca2+ Mobilization in Primary Human Keratinocytes.

Immunoregulatory effects of IL-4/IL-13 and alterations of keratinocyte differentiation are important factors in the pathogenesis of atopic dermatitis (AD). This study investigated the role of IL-4/IL-13 in keratinocyte responses to changes in extracellular Ca2+ and analyzed differentiation signals elicited via Ca2+ sensor, SPARC related modular calcium binding protein 1 (SMOC1). Real time dynamics of transmembrane Ca2+ influx were assessed in live keratinocytes by flow cytometry and microscopy. Exposure of keratinocytes to a high Ca2+ environment (1.3mM) triggered a rapid intracellular Ca2+ influx, while IL-4/IL-13-treated cells exhibited a significant decrease in the peak amplitude of Ca2+ influx (p\u003c0.01). IL-17A and IL-22 did not elicit such responses. Evaluation of intracellular Ca2+ dynamics by microscopy confirmed these observations and revealed heterogeneity of individual keratinocyte responses. IL-4/IL-13 significantly inhibited the expression of Ca2+-binding protein SMOC1 (p\u003c0.001). Inhibition of epidermal differentiation markers were also observed in SMOC1 siRNA-transfected keratinocytes. Concurrently, the deletion of SMOC1 increased the amplitude of Ca2+ peak response (p\u003c0.05). In conclusion, our results provide innovative data that IL-4/IL-13 regulate keratinocyte sensitivity to microenviromental Ca2+ changes and inhibit Ca2+-induced keratinocyte differentiation signals. SMOC1 inhibition by IL-4/IL-13 alters Ca2+ transport in keratinocytes and inhibits differentiation, suggesting a new target for treatment of AD.