IL28RA inhibits human epidermal keratinocyte proliferation by inhibiting cell cycle progression
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Interleukin (IL) 28 receptor α (IL28RA) is a well-known candidate for psoriasis susceptibility based on previous genome-wide association study (GWAS) analysis. However, the function of IL28RA in psoriasis has not been elucidated. In the present study, the expression of IL28RA was significantly decreased in lesional tissues from patients with plaque psoriasis when compared with the expression observed in adjacent non-lesional tissues. In vitro studies further demonstrated that in the presence of IL-29, HaCaT keratinocytes with IL28RA knockdown exhibited a faster rate of proliferation than control cells, and an enhanced ratio of cells in the S and G2/M phase. By contrast, IL28RA overexpression inhibited the proliferation of HaCaT keratinocytes and caused cell cycle arrest at the G0/G1 phases. Western blot analysis revealed that knockdown of IL28RA upregulated cyclinB1 expression and downregulated cyclinE expression; the opposite results were observed in the IL28RA-overexpressing HaCaT cells. Finally, a mechanistic study revealed that IL28RA functions through the activation of the Janus kinase-signal transducer and activator of transcription signaling pathway to exert its anti-proliferative effect. These results suggested that weak expression of IL28RA may contribute to the pathogenesis of psoriasis and that IL28RA may be an effective drug target for the treatment of psoriasis. However, further in vivo studies are required.
KeywordsPsoriasis Interleukin 28 receptor α Proliferation Interleukin-29 Signaling pathway
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81130031 and 81602397) and the Natural Science Foundation of Shanghai (Grant No. 15ZR1405700). Grant Recipient: Xuejun Zhang, Yaohua Zhang.
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Conflict of interest
The authors declare that they have no conflict of interest.
- 11.Li Y, Cheng H, Zuo XB, Sheng YJ, Zhou FS, Tang XF et al (2013) Association analyses identifying two common susceptibility loci shared by psoriasis and systemic lupus erythematosus in the Chinese Han population. J Med Genet 50(12):812–818. https://doi.org/10.1136/jmedgenet-2013-101787 CrossRefGoogle Scholar
- 14.Witte K, Gruetz G, Volk HD, Looman AC, Asadullah K, Sterry W et al (2009) Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines. Genes Immun 10(8):702–714. https://doi.org/10.1038/gene.2009.72 CrossRefGoogle Scholar
- 15.Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R (2007) Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the JAK-STAT pathway and the mitogen-activated protein kinases. J Virol 81(14):7749–7758. https://doi.org/10.1128/JVI.02438-06 CrossRefGoogle Scholar
- 17.Duong FH, Trincucci G, Boldanova T, Calabrese D, Campana B, Krol I et al (2014) IFN-λ receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-λ3 genotype and with nonresponsiveness to IFN-α therapies. J Exp Med 211(5):857–868. https://doi.org/10.1084/jem.20131557 CrossRefGoogle Scholar
- 19.Yang L, Luo Y, Wei J, He S (2010) Integrative genomic analyses on IL28RA, the common receptor of interferon-lambda1, -lambda2 and -lambda3. Int J Mol Med 25(5):807–812Google Scholar
- 21.Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM et al (2005) IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. Am J Physiol Gastrointest Liver Physiol 289(5):G960–G968. https://doi.org/10.1152/ajpgi.00126.2005 CrossRefGoogle Scholar
- 28.Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC (2004) Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-λ. J Biol Chem 279(31):32269–32274. https://doi.org/10.1074/jbc.M404789200 CrossRefGoogle Scholar
- 30.Lowes MA, Suárez-Fariñas M, Krueger JG (2014) Immunology of psoriasis. Annu Rev Immunol 32:227–255. https://doi.org/10.1146/annurev-immunol-032713-120225 CrossRefGoogle Scholar