SMOC1 and IL-4 and IL-13 Cytokines Interfere with Ca2+ Mobilization in Primary Human Keratinocytes.

Abstract

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 (Ca2+) and analyzed differentiation signals elicited via a Ca2+ sensor, SMOC1. Real-time dynamics of transmembrane Ca2+ influx were assessed in live KCs by flow cytometry and microscopy. Exposure of KCs to a high Ca2+ environment (1.3 mM) triggered a rapid intracellular Ca2+ influx, whereas IL-4- and IL-13-treated cells exhibited a significant decrease in the peak amplitude of Ca2+ influx (P < 0.01). 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 KC responses. IL-4 and IL-13 significantly inhibited the expression of Ca2+-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 Ca2+ peak response (P < 0.05). In conclusion, our results provide innovative data that IL-4 and IL-13 regulate KC sensitivity to microenvironmental Ca2+ changes and inhibit Ca2+-induced KC differentiation signals. SMOC1 inhibition by IL-4 and IL-13 alters Ca2+ transport in KCs and inhibits differentiation, suggesting a new target for treatment of atopic dermatitis.

• Authors: Taras Lyubchenko, Hannah K Collins, Kathryn A Vang, Donald Y M Leung, Elena Goleva
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 7 Pg. 1792-1801.e5 (07 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 33484701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• IL13 protein, human
• IL4 protein, human
• Interleukin-13
• Osteonectin
• SMOC1 protein, human
• Interleukin-4
• Calcium

Topics

• Calcium (metabolism)
• Cell Differentiation (immunology)
• Cell Proliferation
• Cells, Cultured
• Dermatitis, Atopic (immunology, pathology)
• Gene Expression Profiling
• Humans
• Interleukin-13 (metabolism)
• Interleukin-4 (metabolism)
• Intravital Microscopy
• Keratinocytes (immunology, metabolism)
• Osteonectin (genetics, metabolism)
• Primary Cell Culture
• Single-Cell Analysis