Skip to main content
SpringerLink
Log in
Book cover

Pharmacology of Itch pp 163–176Cite as

Role of Cytokines and Chemokines in Itch

  • Chapter

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 226))

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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Brandt EB, Sivaprasad U (2011) Th2 cytokines and atopic dermatitis. J Clin Cell Immunol 2(3)

    Google Scholar 

  • Cantrell DA, Smith KA (1984) The interleukin-2 T-cell system: a new cell growth model. Science 224(4655):1312–1316

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Drory VE, Lev D et al (1998) Neurotoxicity of isolated limb perfusion with tumor necrosis factor. J Neurol Sci 158(1):1–4

    Article  CAS  PubMed  Google Scholar 

  • Empl M, Renaud S et al (2001) TNF-alpha expression in painful and nonpainful neuropathies. Neurology 56(10):1371–1377

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Gaspari AA, Lotze MT et al (1987) Dermatologic changes associated with interleukin 2 administration. JAMA 258(12):1624–1629

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Homey B, Steinhoff M et al (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118(1):178–189

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lacreusette A, Nguyen JM et al (2007) Loss of oncostatin M receptor beta in metastatic melanoma cells. Oncogene 26(6):881–892

    Article  CAS  PubMed  Google Scholar 

  • Leyva-Castillo JM, Hener P et al (2013) Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade. Nat Commun 4:2847

    Article  PubMed  Google Scholar 

  • Lippert U, Hoer A et al (1998) Role of antigen-induced cytokine release in atopic pruritus. Int Arch Allergy Immunol 116(1):36–39

    Article  CAS  PubMed  Google Scholar 

  • Luger TA, Stadler BM et al (1981) Epidermal cell (keratinocyte)-derived thymocyte-activating factor (ETAF). J Immunol 127(4):1493–1498

    CAS  PubMed  Google Scholar 

  • Madan V, Griffiths CE (2007) Systemic cyclosporine and tacrolimus in dermatology. Dermatol Ther 20(4):239–250

    Article  CAS  PubMed  Google Scholar 

  • Martin HA (1996) Bradykinin potentiates the chemoresponsiveness of rat cutaneous C-fibre polymodal nociceptors to interleukin-2. Arch Physiol Biochem 104(2):229–238

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Silver JS, Hunter CA (2010) gp130 at the nexus of inflammation, autoimmunity, and cancer. J Leukoc Biol 88(6):1145–1156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Stander S, Steinhoff M (2002) Pathophysiology of pruritus in atopic dermatitis: an overview. Exp Dermatol 11(1):12–24

    Article  CAS  PubMed  Google Scholar 

  • Steinhoff M, Bienenstock J et al (2006) Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol 126(8):1705–1718

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Tamura S, Morikawa Y et al (2002) Expression of oncostatin M in hematopoietic organs. Dev Dyn 225(3):327–331

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • van Joost T, Stolz E et al (1987) Efficacy of low-dose cyclosporine in severe atopic skin disease. Arch Dermatol 123(2):166–167

    Article  PubMed  Google Scholar 

  • Wagner R, Myers RR (1996) Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7(18):2897–2901

    Article  CAS  PubMed  Google Scholar 

  • Wahlgren CF, Scheynius A et al (1990) Antipruritic effect of oral cyclosporin A in atopic dermatitis. Acta Derm Venereol 70(4):323–329

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Zhang JM, An J (2007) Cytokines, inflammation, and pain. Int Anesthesiol Clin 45(2):27–37

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Department of Dermatology, Dept. of Dermatology and UCD Charles Institute of Translational Dermatology University College Dublin (UCD), Belfield, Dublin 4, Ireland

      Eoin R. Storan, Susan M. O’Gorman, Ian D. McDonald & Martin Steinhoff

    Authors
    1. Eoin R. Storan
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Susan M. O’Gorman
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ian D. McDonald
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Martin Steinhoff
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Martin Steinhoff .

    Editor information

    Editors and Affiliations

    1. Department of Pharmacology Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

      Alan Cowan

    2. Department of Dermatology, Temple University School of Medicine, Philadephia, Pennsylvania, USA

      Gil Yosipovitch

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2015 Springer-Verlag Berlin Heidelberg

    About this chapter

    Cite this chapter

    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

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation