TY - JOUR
T1 - Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes
AU - Ehst, Benjamin
AU - Wang, Zhiping
AU - Leitenberger, Justin
AU - McClanahan, Danielle
AU - De La Torre, Rachel
AU - Sawka, Erika
AU - Ortega-Loayza, Alex G.
AU - Strunck, Jennifer
AU - Greiling, Teri
AU - Simpson, Eric
AU - Liu, Yuangang
N1 - Funding Information:
We thank Melanie Swinson for procuring clinical samples and Clara Stemwedel for editing the manuscript. This study was partially supported by NIAMS R03 AR066736, and R01 AR070645.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/2
Y1 - 2021/2
N2 - IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.
AB - IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.
KW - Epidermal growth factor (EGF)
KW - Interleukin 17A (IL-17A)
KW - Keratinocytes
KW - Psoriasis
KW - Tumor necrosis factor alpha (TNFα)
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U2 - 10.1016/j.cyto.2020.155357
DO - 10.1016/j.cyto.2020.155357
M3 - Article
C2 - 33153894
AN - SCOPUS:85095566236
SN - 1043-4666
VL - 138
JO - Cytokine
JF - Cytokine
M1 - 155357
ER -