Trends in Immunotherapy

Article

IL-27 regulates cytokine production as a double-edged sword in keratinocytes

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https://doi.org/10.24294/ti.v6.i1.1436
Aioi, A., & Imamichi, T. (2022). IL-27 regulates cytokine production as a double-edged sword in keratinocytes. Trends in Immunotherapy, 6(1). https://doi.org/10.24294/ti.v6.i1.1436
Volume 6 Issue 1 (2022)

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Authors

  • Akihiro Aioi
    Septem-Soken
  • Tomozumi Imamichi Septem-Soken

Inflammaging is a subject of considerable attention, because aging is characterized by low-grade, chronic, and asymptomatic inflammation, concomitant with increased blood levels of senescence-associated secretory phenotype (SASP) factors, including IL-1, IL-6, IL-8, IL-18, and tumor necrosis factor-α (TNF-α). However, IL-27 is currently not categorized as a SASP factor, although it is known to play pleiotropic roles in inflammation. In this study, we evaluated the interaction between TNF-α and IL-27 in the context of low-grade inflammation using HaCaT cells. TNF-α induced significant upregulation of the mRNA levels of IL-6 and IL-8 at the experimental concentration (~10 ng/ml), while the mRNA levels of IL-1RA, IL-10, and IL-18BP were unchanged. After confirming the expression of functional IL-27 receptors in HaCaT cells, we examined the effects of IL-27 alone on cytokine expression. IL-27 alone significantly upregulated the mRNA levels of IL-10, IL-18BP and IL-6 by 1.61-fold, 1.46-fold, and 2.32-fold, respectively. In the presence of 100 ng/ml of IL-27, the mRNA levels of the anti-inflammatory cytokines IL-1RA, IL-10, and IL-18BP, were significantly upregulated upon treatment with TNF-α at the physiological concentration (1 ng/ml). Taken together, this study indicates that a high concentration of IL-27 exhibits anti-inflammatory effects in the presence of a low concentration of TNF-α in keratinocytes, suggesting that the anti-inflammatory role of IL-27 in inflammaging may be regulated by TNF-α concentration.

Keywords:

IL-27 Keratinocyte Pleiotropic Function Inflammaging

References

  1. Pflanz S, Hibbert L, Mattson J, et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. The Journal of Immunology 2004; 172(4): 2225–2231. doi: 10.4049/jimmunol.172.4.2225
  2. Takeda A, Hamano S, Yamanaka A, et al. Cutting edge: Role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. The Journal of Immunology 2003; 170(10): 4886–4890. doi: 10.4049/jimmunol.170.10.4886
  3. Hibbert L, Pflanz S, Malefyt RDM, et al. IL-27 and IFN-γ signal via Stat1 and Stat3 and induce T-Bet and IL-12Rα2 in naive T cells. Journal of Interferon & Cytokine Research 2003; 23: 513–522. doi: 10.1089/10799900360708632
  4. Kamiya S, Owaki T, Morishima N, et al. An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells. The Journal of Immunology 2004; 173(6): 3871–3877. doi: 10.4049/jimmunol.173.6.3871
  5. Owaki T, Asakawa M, Morishima N, et al. STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of pro-inflammatory cytokine production. The Journal of Immunology 2008; 180(5): 2903–2911. doi: 10.4049/jimmunol.180.5.2903
  6. Pflanz S, Timans JC, Cheung J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 2002; 16(6): 779–790. doi: 10.1016/s1074-7613(02)00324-2
  7. Mei Y, Lv Z, Xiong L, et al. The dual role of IL-27 in CD4+T cells. Molecular Immunology 2021; 138: 172–180. doi: 10.1016/j.molimm.2021.08.001
  8. Stumhofer JS, Hunter CA. Advances in understanding the anti-inflammatory properties of IL-27. Immunology Letters 2008; 117(2): 123–130. doi: 10.1016/j.imlet.2008.01.011
  9. Yoshimura T, Takeda A, Hamano S, et al. Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of pro-inflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. The Journal Immunology 2006; 177(8): 5377–5385. doi: 10.4049/jimmunol.177.8.5377
  10. Swaminathan S, Dai L, Lane HC, et al. Evaluating the potential of IL-27 as a novel therapeutic agent in HIV-1 infection. Cytokine Growth Factor Reviews 2013; 24(6): 571–577. doi: 10.1016/j.cytogfr.2013.07.001
  11. Yang B, Suwanpradid J, Sanchez-Lagunes R, et al. IL-27 facilitates skin wound healing through induction of epidermal proliferation and host defense. Journal of Investigative Dermatology 2017; 137(5): 1166–1175. doi: 10.1016/j.jid.2017.01.010
  12. Wittmann M, Zeitvogel J, Wang D, et al. IL-27 is expressed in chronic human eczematous skin lesions and stimulates human keratinocytes. Journal of Allergy Clinical Immunology 2009; 124(1): 81–89. doi: 10.1016/j.jaci.2009.04.026
  13. Shibata S, Tada Y, Kanda N, et al. Possible roles of IL-27 in the pathogenesis of psoriasis. Journal of Investigative Dermatology 2010; 130(4): 1034–1039. doi: 10.1038/jid.2009.349
  14. Jergović M, Thompson HL, Bradshaw CM, et al. IL-6 can singlehandedly drive many features of frailty in mice. GeroScience 2021; 43: 539–549. doi: 10.1007/s11357-021-00343-z
  15. Marcos-Pérez D, Sánchez-Flores M, Maseda A, et al. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Frontiers in Immunology 2018; 9: 1056. doi: 10.3389/fimmu.2018.01056
  16. Van Epps PV, Oswald D, Higgins PA, et al. Frailty has a stronger association with inflammation than age in older veterans. Immunity and Ageing 2016; 13: 27. doi: 10.1186/s12979-016-0082-z
  17. Xia S, Zhang X, Zheng S, et al. An update on inflamm-aging: mechanisms, prevention, and treatment. Journal of Immunology Research 2016; 2016: 8426874. doi: 10.1155/2016/8426874
  18. Bektas A, Schurman SH, Sen R, et al. Aging, inflammation and the environment. Experimental Gerontology 2018; 105: 10–18. doi: 10.1016/j.exger.2017.12.015
  19. Minciullo PL, Catalano A, Mandraffino G, et al. Inflammaging and anti-inflammaging: The role of cytokines in extreme longevity. Archivum Immunologiae et Therapiae Experimentalis 2016; 64: 111–126. doi: 10.1007/s00005-015-0377-3
  20. Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular senescence: causes and consequences. Trends in Molecular Medicine 2010; 16(5): 238–246. doi: 10.1016/j.molmed.2010.03.003
  21. Aioi A. Inflammaging in skin and intrinsic underlying factors. Trends in Immunotherapy 2021; 5(2): 44–53. doi: 10.24294/ti.v5.i2.1342
  22. Deyrieux AF, Wilson VG. In vitro culture conditions to study keratinocyte differentiation using the HaCaT cell line. Cytotechnology 2007; 54: 77–83. doi: 10.1007/s10616-007-9076-1
  23. Yamada T, Aioi A. Eucalyptus citriodora extract regulates cutaneous homeostasis including immune dysregulation and skin barrier dysfunction via the modulation of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) pathway. Trends in Immunotherapy 2020; 4(2): 69–80. doi: 10.24294/ti.v4.i2.1130
  24. Aioi A, Muromoto R, Mogami S, et al. Porcine placenta extract reduced wrinkle formation by potentiating epidermal hydration. Journal of Cosmetics, Dermatological Sciences and Applications 2021; 11(2): 101–109. doi: 10.4236/jcdsa.2021.112011
  25. Zanni F, Vescovini R, Biasini C, et al. Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: A contribution to understand the relationship between inflammation and immunosenescence. Experimental Gerontology 2003; 38(9): 981–987. doi: 10.1016/s0531-5565(03)00160-8
  26. Kalliolias GD, Gordon RA, Ivashkiv LB. Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27. The Journal of Immunology 2010; 185: 7047–7056. doi: 10.4049/jimmunol.1001290
  27. Fujiwara S, Nagai H, Oniki S, et al. Interleukin (IL)-17 versus IL-27: Opposite effects on tumor necrosis factor-α-mediated chemokine production in human keratinocytes. Experimental Dermatology 2012; 21(1): 70–72. doi: 10.1111/j.1600-0625.2011.01384.x
  28. De Groot M, Teunissen MBM, Picavet DI, et al. Reduction of different inflammatory cell types of the innate immune system in psoriatic skin during etanercept treatment. Experimental Dermatology 2010; 19: 754–756. doi: 10.1111/j.1600-0625.2010.01089.x
  29. Batten M, Kljavin NM, Li J, et al. Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. The Journal of Immunology 2008; 180(5): 2752–2756. doi: 10.4049/jimmunol.180.5.2752
  30. Wittmann M, Doble R, Bachmann M, et al. IL-27 regulates IL-18 binding protein in skin resident cells. PLoS ONE 2012; 7: e38751. doi: 10.1371/journal.pone.0038751
  31. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg Jv, et al. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. The American Journal of Medicine 2003; 115(4): 278–283. doi: 10.1016/s0002-9343(03)00329-2
  32. He H, Xu P, Zhang X, et al. Aging-induced IL27Ra signaling impairs hematopoietic stem cells. Blood 2020; 136(2): 183–198. doi: 10.1182/blood.2019003910
  33. Boehmer ED, Meehan MJ, Cutro BT, et al. Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway. Mechanisms of Ageing and Development 2005; 126(12): 1305–1313. doi: 10.1016/j.mad.2005.07.009
  34. Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 2016; 17: 7–19. doi: 10.1007/s10522-015-9578-8