The role of cytokines in AD & PN

The Role of Cytokines in AD and PN

The discovery of IgE provides the first indication of immune system involvement in AD pathophysiology​ Type 2 cytokines, IL-4 and IL-13, and their signaling pathways are discovered​ IL-4 and IL-13 are produced by a broad range of cells and are involved in AD and PN pathophysiology​ IL-31 is discovered and is produced by a broad range of cells​ IL-31 is known as an itch cytokine​ IL-31 mediates inflammation and skin barrier disruption​
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The discovery of IgE provides the first indication of immune system involvement in AD pathophysiology​
The discovery of IgE provides the first indication of immune system involvement in AD pathophysiology​

1967​

IgE discovered​

The immune system is involved in allergic/atopic diseases.1​

​ 1978​

Immune system is implicated in AD​.

Dermal and serum IgE levels are linked to AD pathophysiology.1,2​

​

Type 2 cytokines, IL-4 and IL-13, and their signaling pathways are discovered​
Type 2 cytokines, IL-4 and IL-13, and their signaling pathways are discovered​

1982-1987​

IL-4 discovered​

  • IL-4, originally referred to as BSF-1, is discovered and shown to promote B cell development and function.3,4​
  • The IL-4 receptor (IL-4R) identified on the surface of T cells mediates IL-4 signaling.5​

1985-1988​

IL-4 is produced by Th2 cells​.

IL-4 is produced by Th2 cells, promotes cell infiltration and mast cell activation, and drives Ig isotope switching to IgG1.6-9​

​

1986-1996​

IL-13 discovered​

IL-4 signaling and function are mediated by IL-13 and through a receptor complex comprising IL-4Rα and IL-13Rα1.4,10

IL-4 and IL-13 are produced by a broad range of cells and are involved in AD and PN pathophysiology​
IL-4 and IL-13 are produced by a broad range of cells and are involved in AD and PN pathophysiology​

1991-1996​

IL-4 is widely expressed by immune cells​.

IL-4 is produced by basophils, eosinophils, CD4+ T cells, and NK1.1+ T cells.11-14​

​

1994​

IL-4 is overexpressed in AD skin​.

IL-4 is linked to inflammation in AD skin.15​

​

2000-2004​

IL-4 and IL-13 are linked to fibrosis​.

IL-4 and IL-13 signaling are involved in collagen production and fibrosis.16,17

 

2001​

IL-4 is mechanistically linked to different aspects of AD pathophysiology​.

IL-4 induces AD-like symptoms including itch, skin lesions, and inflammation in transgenic mouse models.18​

​

2009​

IL-13 is linked to different aspects of AD pathophysiology​

IL-13 induces skin lesions, inflammation, skin remodeling, and fibrosis in transgenic mouse models.19

IL-31 is discovered and is produced by a broad range of cells​
IL-31 is discovered and is produced by a broad range of cells​

2004​

IL-31 discovered​

  • IL-31 was first described as a Th2 cytokine20​
  • The IL-31 receptor, a heterodimer composed of IL-31Rα and the oncostatin M receptor (OSMR), mediates IL-31 signaling.20​

​

2010-2022​

IL-31 is produced by multiple immune cells​.

Th1 cells, mast cells, basophils, eosinophils, dendritic cells, and innate lymphoid cells can produce IL-31.21-27

IL-31 is known as an itch cytokine
IL-31 is known as an itch cytokine​

2004-2014​

IL-31 promotes itch.28​

  • IL-31 is the first cytokine recognized to directly mediate itch and act as a pruritogen.20,29​
  • IL-31 is involved in the pathophysiology of dermatologic disease accompanied by itch.28,29​
  • IL-31 promotes itch by interacting with sensory nerves and keratinocytes in the skin.28​

​

2016​

IL-31 induces structural changes in sensory neurons​.

IL-31 induces a distinct transcriptional program leading to nerve elongation and branching in sensory neurons.30

IL-31 mediates inflammation and skin barrier disruption​
IL-31 mediates inflammation and skin barrier disruption​

2007-2010​

IL-31 contributes to inflammation​.

IL-31 contributes to inflammatory responses and mediates cross talk between eosinophils and keratinocytes.31-33​

​

2012-2021​

IL-31 contributes to skin barrier disruption, tissue remodeling, and fibrosis.34​

  • IL-31 signaling increases epidermal cell proliferation and thickening, impairs keratinocyte differentiation, and decreases filaggrin expression, leading to skin barrier disruption.34​
  • IL-31 induces genes involved in proliferation and tissue remodeling in dermal basal cells and boosts collagen production in dermal fibroblasts.34,35
  1. Kramer ON, Strom MA, Ladizinski B, Lio PA. The history of atopic dermatitis. Clin Dermatol. 2017;35(4):344-348. doi:10.1016/j.clindermatol.2017.03.005​
  2. Taïeb A, Wallach D, Tilles G. The history of atopic eczema/dermatitis. In: Ring J, Przybilla B, Ruzicka T, eds. Handbook of Atopic Eczema. Springer; 2006.​
  3. Howard M, Farrar J, Hilfiker M, et al. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982;155(3):914-923. doi:10.1084/jem.155.3.91​
  4. Paul WE. History of interleukin-4. Cytokine. 2015;75(1):3-7. doi:10.1016/j.cyto.2015.01.038​
  5. Ohara J, Paul WE. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature. 1987;325(6104):537-540. doi:10.1038/325537a0​
  6. Coffman RL, Ohara J, Bond MW, et al. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol.​   1986;136(12):4538-4541.​
  7. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136(7):2348-2357.​
  8. Sideras P, Bergstedt-Lindqvist S, Severinson E. Partial biochemical characterization of IgG1-inducing factor. Eur J Immunol. 1985;15(6):593-598. doi:10.1002/eji.1830150612​
  9. Lebman DA, Coffman RL. Interleukin 4 causes isotype switching to IgE in T cell-stimulated clonal B cell cultures. J Exp Med. 1988;168(3):853-862. doi:10.1084/jem.168.3.853​
  10. Hilton DJ, Zhang JG, Metcalf D, et al. Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc Natl Acad Sci U S A. 1996;93(1):497-501. doi:10.1073/pnas.93.1.497​
  11. Seder RA, Paul WE, Dvorak AM, et al. Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils. Proc Natl Acad Sci U S A. 1991;88(7):2835-2839. doi:10.1073/pnas.88.7.2835
  12. Yoshimoto T, Paul WE. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3.​ J Exp Med. 1994;179(4):1285-1295. doi:10.1084/jem.179.4.1285​
  13. Nonaka M, Nonaka R, Woolley K, et al. Distinct immunohistochemical localization of IL-4 in human inflamed airway tissues. IL-4 is localized to eosinophils in vivo and is released by peripheral blood eosinophils. J Immunol. 1995;155(6):3234-3244.​
  14. Bjerke T, Gaustadnes M, Nielsen S, et al. Human blood eosinophils produce and secrete interleukin 4. Respir Med. 1996;90(5):271-277. doi:10.1016/S0954-6111(96)90098-0​
  15. Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest.​1994;94(2):870-876. doi:10.1172/JCI117408​
  16. Oriente A, Fedarko NS, Pacocha SE, et al. Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. J Pharmacol Exp Ther.  2000; 292(3):988-994.​
  17. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583-594. doi:10.1038/nri1412​
  18. Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001;117(4):977-983. doi:10.1046/j.0022-202x.2001.01484.x​
  19. Zheng T, Oh MH, Oh SY, et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009;129(3):742-751. doi:10.1038/jid.2008.295​
  20. Dillon SR, Sprecher C, Hammond A, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5(7):752-760. doi:10.1038/ni1084​
  21. Stott B, Lavender P, Lehmann S, et al. Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation. J Allergy Clin Immunol.​ 2013;132(2):446-454.e5. doi:10.1016/j.jaci.2013.03.050​
  22. Niyonsaba F, Ushio H, Hara M, et al. Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol. 2010;184(7):3526-3534. doi:10.4049/jimmunol.0900712​
  23. Raap U, Gehring M, Kleiner S, et al. Human basophils are a source of—and are differentially activated by—IL-31. Clin Exp Allergy. 2017;47(8):499-508. doi:10.1111/cea.12875​
  24. Kunsleben N, Rüdrich U, Gehring M, et al. IL-31 induces chemotaxis, calcium mobilization, release of reactive oxygen species, and CCL26 in eosinophils, which are capable to release IL-31. J Invest Dermatol. 2015;135(7):1908-1911. doi:10.1038/jid.2015.106​
  25. Cevikbas F, Wang X, Akiyama T, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1.​ J Allergy Clin Immunol. 2014;133(2):448-460. doi:10.1016/j.jaci.2013.10.048​
  26. Che DN, Cho BO, Kim JS, et al. Effect of luteolin and apigenin on the production of Il-31 and Il-33 in lipopolysaccharides-activated microglia cells and their mechanism of action. Nutrients. 2020;12(3):811. doi: 10.3390/nu12030811​
  27. Alkon N, Bauer WM, Krausgruber T, et al. Single-cell analysis reveals innate lymphoid cell lineage infidelity in atopic dermatitis. J Allergy Clin Immunol. 2022;149(2):624-639. doi:10.1016/j.jaci.2021.07.025​
  28. Lee CH, Hong CH, Yu WT, et al. Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide β-endorphin, via STAT3/calcium axis in atopic dermatitis. Br J Dermatol. 2012;167(4):794-803. doi:10.1111/j.1365-2133.2012.11047.x​
  29. Trier AM, Kim BS. Cytokine modulation of atopic itch. Curr Opin Immunol. 2018;54:7-12. doi:10.1016/j.coi.2018.05.005​
  30. Feld M, Garcia R, Buddenkotte J, et al. The pruritus- and TH2-associated cytokine IL-31 promotes growth of sensory nerves. J Allergy Clin Immunol.   2016;138(2):500-508.e24. doi:10.1016/j.jaci.2016.02.020​
  31. Dambacher J, Beigel F, Seiderer J, et al. Interleukin 31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is upregulated in inflammatory bowel disease. Gut. 2007;56(9):1257-1265. doi:10.1136/gut.2006.118679
  32. Cheung PF, Wong CK, Ho AW, et al. Activation of human eosinophils and epidermal keratinocytes by Th2 cytokine IL-31: implication for the immunopathogenesis of atopic dermatitis. Int Immunol. 2010;22(6):453-467. doi:10.1093/intimm/dxq027​
  33. Kasraie S, Niebuhr M, Werfel T. Interleukin (IL)-31 induces pro-inflammatory cytokines in human monocytes and macrophages following stimulation with staphylococcal exotoxins. Allergy. 2010;65(6):712-721.​
  34. Singh B, Jegga AG, Shanmukhappa KS, et al. IL-31-driven skin remodeling involves epidermal cell proliferation and thickening that lead to impaired skin- barrier function. PloS One. 2016;11(8):e0161877. doi:10.1371/journal.pone.0161877​
  35. Hänel KH, Pfaff CM, Cornelissen C, et al. Control of the physical and antimicrobial skin barrier by an IL-31-IL-1 signaling network. J Immunol.​2016;196(8):3233-3244. doi:10.4049/jimmunol.1402943

References:

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