Ann Dermatol.  2021 Apr;33(2):122-130. 10.5021/ad.2021.33.2.122.

I-Kappa-B-Zeta Regulates Interleukin-17A/ Tumor Necrosis Factor-Alpha Mediated Synergistic Induction of Interleukin-19 and Interleukin-20 in Humane Keratinocytes

• Bertelsen T
• Iversen L
• Johansen C

• KMID: 2513593
• DOI: http://doi.org/10.5021/ad.2021.33.2.122

Abstract

Background
Interleukin (IL)-19 and IL-20 are important members of the IL-10 cytokine family, which are known to play a role in inflammatory processes. Both anti-IL-19 and -IL-20 targeting drugs have been suggested in the treatment of inflammatory diseases such as psoriasis and rheumatoid arthritis. Recently, we presented I-kappa-B-zeta (IκBζ) as a key player in psoriasis by identifying IκBζ as a regulator of IL-17/tumor necrosis factor (TNF)α-inducible psoriasisassociated genes and proteins. Some of these genes were synergistically regulated by IL-17/TNFα.
Objective
The purpose of this study was to explore the role of IκBζ in the regulation of IL-17A/TNFα-mediated induction of IL-19 and IL-20 expression in human keratinocytes.
Methods
In vitro experiments with cultured primary humane keratinocytes were conducted and investigated by quantitative polymerase chain reaction (qPCR), Western blotting, ELISA and EMSA. For statistics, a one- or two- way repeated-measures analysis of variance (RM ANOVA) or the Friedman test (a nonparametric equivalent to the RM ANOVA) were conducted.
Results
We demonstrated that IL-19 and IL-20 mRNA and protein expressions were synergistically induced by IL-17A and TNFα, whereas IL-17A and TNFα alone had only a minor effect on the IL-19 and IL-20 expression. Moreover, we demonstrated IκBζ to be a regulator of this synergistic induction of IL-19 and IL-20. Finally, the IL-17A/TNFα-induced synergistic induction of IL-19 and IL-20 expression was found to be mediated by a p38 MAPK-, NF-κB- and JNK1/2-dependent mechanism.
Conclusion
This study demonstrates that IκBζ plays a role in the IL-17A/TNFα-mediated synergistic induction of IL-19 and IL-20 in humane keratinocytes.

Keyword

I-kappa-B-zeta; Interleukin-17A; Interleukin-19; Interleukin-20; NFKBIZ