Upstream eventOverproduction of IL-23
Overproduction of IL-17
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Stimulation of TLR7/8 in dendric cells leading to Psoriatic skin disease||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
IL-23 is important for differentiation and proliferation of Th17 cells. As a major source of IL-23, Tip-DC is present in the skin lesions of psoriatic patients and works to activate the Th17 pathway (Hansel et al. 2011).
Signaling through the heterodimeric IL-23 receptor (subunits of p19 and p40) of Th17 cells stimulates the production of proinflammatory keratinocyte cytokines that mediate the psoriatic response and induces the production of IL-17. Th17 cells are increased in the peripheral blood and lesion skin of psoriatic patients, and IL-17 and IL-22 produced from Th17 act on epidermal keratinocytes to cause inflammatory chemokines and hyperproliferation (Michelle A. et al. 2005).
IL-17A, which is highly expressed by Th17 cells, has a direct effect on the regulation of genes expressed by keratinocytes that are involved in innate immune defense, including defensins,8, 9 S100 family proteins, lipocalin, and LL37/cathelicidin, as well as a range of CXCL chemokines that regulate neutrophil trafficking (Gilliet et al. 2004). IL-22, which is expressed by Th22 and Th17 cells, and related IL-20 family members promote keratinocyte hyperproliferation and abnormal differentiation (Krueger et al. 2012).
Evidence Supporting this KER
IL-17A, which is highly expressed by TH17 cells, has a direct effect on the regulation of genes expressed by keratinocytes that are involved in innate immune defense, thorough expressions of defensins,8, 9, S100 family proteins, lipocalin and LL37/cathelicidin, as well as a range of CXCL chemokines that regulate neutrophil trafficking. IL-22, which is expressed by TH22 and TH17 cells, and related IL-20 family members promote keratinocyte hyperproliferation and abnormal differentiation （Gilliet et al.2012）.
In vitro Reconstituted Human Epidermis (RHE) model stimulated for 48 hours with medium containing IL-17, IL-22 and TNFα mix (concentration 3 ng / mL) as psoriasis-specific cytokines. Controls were cultured in normal medium. After fixing RHE and embedding in paraffin, 4 μm sections were stained with hematoxylin-eosin or immunolabeled with anti-filaggrin, anti-S100A7, anti-hBD-2 mAb.
RHE stimulated with cytokine mix showed dramatic expression of these protein. In the RHE with normal medium, antibacterial peptide S100A7 was expressed locally, but BD-2 protein was not detected. This is due to the synergistic effect of IL-17 added to the IL-22 / TNFα combination. Filaggrin, S100A7 and BD-2 mRNA expression by RT-qPCR analysis increased 20-fold (S100A7) or -50-fold (BD-2) compared to controls. This is a downstream event that can be modeled using keratinocytes and cytokines and relies on upstream mechanisms of recruitment and activation of other innate adaptive immune cells.（Bernard et al. 2012.）.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
IL-23, which maintains Th17 cells, is released from TNF-a and inducible nitric oxide synthase (iNOS) -producing dendritic cells (TIP-DC). TIP-DC activates IL-17, IL-22, IL-23, and TNF-a mRNA expression in psoriatic skin. Cytokine staining analysis of peripheral blood mononuclear cell (PBMC) in patients with psoriasis showed a three-fold increase in Th17 cells compared to normal PBMC. Thl7 cells produce IL-22 and stimulate keratinocyte proliferation. IL-22 activates STAT3 and induces the production of cytokine (such as IL-8), chemokines and the synthesis of antimicrobial peptides (Zaba et al. 2005).
The epidermis of psoriasis patients did not have many T cells, but the analysis was similar to peripheral blood and dermis. The proportion of Th17 cells in the dermis was significantly higher than that in normal skin, and TNF and IFN-g were produced from Th17 cells. Skin and peripheral blood contained a subset of Th17 cells producing IFN-g / TNF.
Keratin 16, IL-17, IFN-g, and IL-22 mRNA expression increased in psoriatic skin, but cyclosporine therapy returned these mRNA to normal levels. The average expression of IL-17 / human acidic ribosomal protein (hARP) in non-lesional skin was 0.4 compared to 10.8 in lesional skin, and cyclosporine administration returned to non-lesional levels. That IL-17 mRNA return to baseline, effective treatment supports that Th17 in psoriasis is a central pathogenic.(Lowes et al.2008)
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
In mice, application of IL-23 causes psoriatic-like epidermal hyperplasia, but this effect does not occur in IL-17A and IL-22KO mice. Therefore, it is thought that IL-17A and IL-22 play an important role downstream of IL-23（Rizzo HL. Et al. 2011）.
Recombinant mIL-23 (rmIL-23) injected into the ear of WT mice induced IL-17A and IL-22 expression, and showed ear swelling and epidermal hyperplasia. When rmIL-23 was injected into IL-22 KO mice, IL-22 was induced, but ear swelling and epidermal hyperplasia were less than in WT mice. When rmIL-23 was injected into IL-17A KO mice, IL-22 was induced, but ear swelling and epidermal hyperplasia hardly occurred. WT mice after administration of IL-22 or IL-17A inhibitor completely inhibited IL-23-induced epidermal hyperplasia. These results indicate that two cytokines, IL-22 and IL-17A, are downstream mediators of IL-23-induced changes in mouse skin and are required for the generation of IL-23-mediated skin lesions. (Hansel et al. 2011)
- Anja Hänsel,Claudia Günther, Jens Ingwersen, Josephine Starke, Marc Schmitz, MichaelBachmann,Michael Meurer, Ernst Peter Rieber, Knut Schäkel. Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong TH17/TH1 T-cell responses.J.Allergy. Clin. Immunol. 2011, 127, 787-794.
- Michelle A. Lowes, Francesca Chamian, Maria Veronica Abello, Judilyn Fuentes-Duculan,Shao-Lee Lin, Rachel Nussbaum, Inna Novitskaya, Henrietta Carbonaro, Irma Cardinale, Toyoko Kikuchi, Patricia Gilleaudeau, Mary Sullivan-Whalen, Knut M. Wittkowski, Kim Papp, Marvin Garovoy, Wolfgang Dummer, Ralph M. Steinman, James G. Kruege. Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 19057–19062.
- James G Krueger, Scott Fretzin, Mayte Suarez-Farinas, Patrick A Haslett, Krista M Phipps, Gregory S Cameron, Juliet Mccolm, Artemis Katcherian, Inna Cueto, Traci White, Subhashis Banerjee, and Robert W Hoffman. IL-17A is essential for cell activation and inflammatory gene ciorcuits in subjects with psoriasis. Jourmal of Allergy and Clinical Immunology 2012, 130(1): 145-154
- Michel Gilliet, Curdin Conrad, Michael Geiges, Antonio Cozzio, Wolfgang Thürlimann, Günter Burg, Frank O. Nestle, Reinhard Dummer. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.Arch.Dermatol.2004, 140, 1490-1495.・Bernard 2012
- Lisa C. Zaba, Irma Cardinale, Patricia Gilleaudeau, Mary Sullivan-Whalen, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Inna Novitskaya, Artemis Khatcherian, Mark J. Bluth, Michelle A. Lowes, James G. Krueger. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 2007, 204, 3183-3194.
- Michelle A. Lowes, Toyoko Kikuchi, Judilyn Fuentes-Duculan, Irma Cardinale, Lisa C. Zaba, Asifa S. Haider, Edward P. Bowman, and James G. Krueger. Psoriasis Vulgaris Lesions Contain Discrete Populations of Th1 and Th17 T Cells. Journal of Investigative Dermatology. 2008, 128, 1207-1211.
- Rizzo HL, Kagami S, Phillips KG, Kurtz SE, Jacques SL, Blauvelt A. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol. 2011 Feb 1; 186(3): 1495-502.