Abstract
Cytokines classically are secreted “messenger” proteins that modulate cellular function of immune cells. Chemokines attract immune cells to the site where they exert various functions in inflammation, autoimmunity or cancer. Increasing evidence is emerging that cytokines or chemokines can act as “neuro-modulators” by activating high-affinity receptors on peripheral or central neurons, microglia cells or Schwann cells. Very recently, cytokines have been shown to act as pruritogens in rodents and humans, while a role of chemokines in itch has thus far been only demonstrated in mice. Upon stimulation, cytokines are released by skin or immune cells and form a “bridge of communication” between the immune and nervous system. For some cytokines such as IL-31 and TSLP, the evidence for this role is strong in rodents. For cytokines such as IL-4, there is some convincing evidence, while for cytokines such as oncostatin M, IL-2, IL-6, IL-8 and IL-13, direct evidence is currently limited. Current clinical trials support the idea that cytokines and chemokines and their receptors or signalling pathways are promising targets for the future therapy of certain subtypes of itch.
Dr. Storan and Dr. O'Gorman both contributed equally to writing the manuscript.
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- AD:
-
Atopic dermatitis
- CLA:
-
Cutaneous lymphocyte-associated antigen
- CD:
-
Cluster of differentiation
- DRG:
-
Dorsal root ganglion
- ET-1:
-
Endothelin 1
- IFNγ:
-
Interferon gamma
- IL:
-
Interleukin
- IL-31RA:
-
IL-31 receptor alpha
- KO:
-
Knockout
- MAPK:
-
Mitogen-activated protein kinase
- mRNA:
-
Messenger RNA
- mrgpr:
-
Mas-related G protein-coupled receptor
- OSM:
-
Oncostatin M
- OSMRβ:
-
OSM receptor beta
- STAT:
-
Signal transducer and activator of transcription
- TH:
-
T helper cells
- TRPA1:
-
Transient receptor channel ankyrin subtype 1
- TRPV1:
-
Transient receptor potential cation channel subfamily V member 1
- TSLP:
-
Thymic stromal lymphopoietin
- SEB:
-
Staphylococcal enterotoxin B
References
Arai I, Tsuji M et al (2013) A single dose of interleukin-31 (IL-31) causes continuous itch-associated scratching behaviour in mice. Exp Dermatol 22(10):669–671
Arita K, South AP et al (2008) Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Am J Hum Genet 82(1):73–80
Bando T, Morikawa Y et al (2006) Complete overlap of interleukin-31 receptor A and oncostatin M receptor beta in the adult dorsal root ganglia with distinct developmental expression patterns. Neuroscience 142(4):1263–1271
Beck LA, Thaci D et al (2014) Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 371(2):130–139
Bilsborough J, Leung DY et al (2006) IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol 117(2):418–425
Boniface K, Diveu C et al (2007) Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol 178(7):4615–4622
Brandt EB, Sivaprasad U (2011) Th2 cytokines and atopic dermatitis. J Clin Cell Immunol 2(3)
Cantrell DA, Smith KA (1984) The interleukin-2 T-cell system: a new cell growth model. Science 224(4655):1312–1316
Cevikbas F, Wang X et al (2014) A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 133(2):448–460
Chan LS, Robinson N et al (2001) 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 117(4):977–983
Cheung PF, Wong CK et al (2010) Activation of human eosinophils and epidermal keratinocytes by Th2 cytokine IL-31: implication for the immunopathogenesis of atopic dermatitis. Int Immunol 22(6):453–467
Cremer B, Heimann A et al (1995) Pruritogenic effects of mitogen-stimulated peripheral blood mononuclear cells in atopic eczema. Acta Derm Venereol 75(6):426–428
Darsow U, Scharein E et al (1997) Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factor-alpha) at the dermal-epidermal junction. Br J Dermatol 137(3):415–417
Dillon SR, Sprecher C et al (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5(7):752–760
Diveu C, Lak-Hal AH et al (2004) Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. Eur Cytokine Netw 15(4):291–302
Dreuw A, Radtke S et al (2004) Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J Biol Chem 279(34):36112–36120
Drory VE, Lev D et al (1998) Neurotoxicity of isolated limb perfusion with tumor necrosis factor. J Neurol Sci 158(1):1–4
Empl M, Renaud S et al (2001) TNF-alpha expression in painful and nonpainful neuropathies. Neurology 56(10):1371–1377
Fallahzadeh MK, Roozbeh J et al (2011) Interleukin-2 serum levels are elevated in patients with uremic pruritus: a novel finding with practical implications. Nephrol Dial Transplant 26(10):3338–3344
Feld M, Shpacovitch VM et al (2010) Interferon-gamma induces upregulation and activation of the interleukin-31 receptor in human dermal microvascular endothelial cells. Exp Dermatol 19(10):921–923
Gaspari AA, Lotze MT et al (1987) Dermatologic changes associated with interleukin 2 administration. JAMA 258(12):1624–1629
George A, Schmidt C et al (1999) Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol 160(1):124–132
Ghilardi N, Li J et al (2002) A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5. J Biol Chem 277(19):16831–16836
Grimstad O, Sawanobori Y et al (2009) Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp Dermatol 18(1):35–43
Grothe C, Heese K et al (2000) Expression of interleukin-6 and its receptor in the sciatic nerve and cultured Schwann cells: relation to 18-kD fibroblast growth factor-2. Brain Res 885(2):172–181
Hamid Q, Boguniewicz M et al (1994) Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 94(2):870–876
Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155
Hawro T, Saluja R et al (2014) Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy 69(1):113–117
Homey B, Steinhoff M et al (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118(1):178–189
Imamachi N, Park GH et al (2009) TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci USA 106(27):11330–11335
Kasraie S, Niebuhr M et al (2010) Interleukin (IL)-31 induces pro-inflammatory cytokines in human monocytes and macrophages following stimulation with staphylococcal exotoxins. Allergy 65(6):712–721
Kasutani K, Fujii E, et al. (2014) Anti-IL-31 receptor antibody is shown to be a potential therapeutic option for treating itch and dermatitis in mice. Br J Pharmacol 171(22):5049–5058
Konishi H, Tsutsui H et al (2002) IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. Proc Natl Acad Sci USA 99(17):11340–11345
Lacreusette A, Nguyen JM et al (2007) Loss of oncostatin M receptor beta in metastatic melanoma cells. Oncogene 26(6):881–892
Leyva-Castillo JM, Hener P et al (2013) Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade. Nat Commun 4:2847
Lippert U, Hoer A et al (1998) Role of antigen-induced cytokine release in atopic pruritus. Int Arch Allergy Immunol 116(1):36–39
Luger TA, Stadler BM et al (1981) Epidermal cell (keratinocyte)-derived thymocyte-activating factor (ETAF). J Immunol 127(4):1493–1498
Madan V, Griffiths CE (2007) Systemic cyclosporine and tacrolimus in dermatology. Dermatol Ther 20(4):239–250
Martin HA (1996) Bradykinin potentiates the chemoresponsiveness of rat cutaneous C-fibre polymodal nociceptors to interleukin-2. Arch Physiol Biochem 104(2):229–238
Morikawa Y, Tamura S et al (2004) Essential function of oncostatin m in nociceptive neurons of dorsal root ganglia. J Neurosci 24(8):1941–1947
Neis MM, Peters B et al (2006) Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol 118(4):930–937
Niyonsaba F, Ushio H et al (2010) Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol 184(7):3526–3534
Nobbe S, Dziunycz P et al (2012) IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. Acta Derm Venereol 92(1):24–28
Nordlind K, Chin LB et al (1996) Immunohistochemical localization of interleukin-6-like immunoreactivity to peripheral nerve-like structures in normal and inflamed human skin. Arch Dermatol Res 288(8):431–435
Paus R, Schmelz M et al (2006) Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest 116(5):1174–1186
Raby BA, Silverman EK et al (2003) Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes. Hum Mol Genet 12(16):1973–1979
Repovic P, Benveniste EN (2002) Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia. J Neurosci 22(13):5334–5343
Schafers M, Sommer C et al (2008) Selective stimulation of either tumor necrosis factor receptor differentially induces pain behavior in vivo and ectopic activity in sensory neurons in vitro. Neuroscience 157(2):414–423
Schulz F, Marenholz I et al (2007) A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopic eczema. J Allergy Clin Immunol 120(5):1097–1102
Shubayev VI, Myers RR (2000) Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury. Brain Res 855(1):83–89
Silver JS, Hunter CA (2010) gp130 at the nexus of inflammation, autoimmunity, and cancer. J Leukoc Biol 88(6):1145–1156
Singer EM, Shin DB et al (2013) IL-31 is produced by the malignant T-cell population in cutaneous T-Cell lymphoma and correlates with CTCL pruritus. J Invest Dermatol 133(12):2783–2785
Sonkoly E, Muller A et al (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 117(2):411–417
Stander S, Steinhoff M (2002) Pathophysiology of pruritus in atopic dermatitis: an overview. Exp Dermatol 11(1):12–24
Steinhoff M, Bienenstock J et al (2006) Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol 126(8):1705–1718
Steinhoff M, Cevikbas F, et al. (2012) Evaluation and management of a patient with chronic pruritus. J Allergy Clin Immunol 130(4): 1015–1016 e1017
Tamura S, Morikawa Y et al (2002) Expression of oncostatin M in hematopoietic organs. Dev Dyn 225(3):327–331
Tanaka M, Hara T et al (1999) Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit. Blood 93(3):804–815
van Joost T, Stolz E et al (1987) Efficacy of low-dose cyclosporine in severe atopic skin disease. Arch Dermatol 123(2):166–167
Wagner R, Myers RR (1996) Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7(18):2897–2901
Wahlgren CF, Scheynius A et al (1990) Antipruritic effect of oral cyclosporin A in atopic dermatitis. Acta Derm Venereol 70(4):323–329
Wahlgren CF, Tengvall Linder M et al (1995) Itch and inflammation induced by intradermally injected interleukin-2 in atopic dermatitis patients and healthy subjects. Arch Dermatol Res 287(6):572–580
Wilson SR, The L et al (2013) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155(2):285–295
Yamaoka K, Okayama Y et al (2009) Proteomic approach to FcepsilonRI aggregation-initiated signal transduction cascade in human mast cells. Int Arch Allergy Immunol 149(Suppl 1):73–76
Zhang JM, An J (2007) Cytokines, inflammation, and pain. Int Anesthesiol Clin 45(2):27–37
Zheng T, Oh MH et al (2009) Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol 129(3):742–751
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Storan, E.R., O’Gorman, S.M., McDonald, I.D., Steinhoff, M. (2015). Role of Cytokines and Chemokines in Itch. In: Cowan, A., Yosipovitch, G. (eds) Pharmacology of Itch. Handbook of Experimental Pharmacology, vol 226. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44605-8_9
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