Abstract
IL-31, predominantly produced by CD45RO + CLA + Th2 cells, plays an important pathogenetic role in pruritic skin diseases like atopic dermatitis. As tumor cells in Sézary syndrome (SS) and Mycosis fungoides (MF) possess similar immunophenotypes and the conditions mentioned are often associated with pruritus, the analysis of the IL-31 pathway in MF/SS patients is of interest. Serum samples from the peripheral blood of 23 patients and 17 controls were analyzed for IL-31 abundance and correlated with disease stage and pruritus. Furthermore IL-31-, IL-31 receptor alpha (IL-31Rα)- and Oncostatin M receptor beta (OSMRβ)-mRNA expression was measured in blood tumor cells from SS patients, memory T-cells from controls and lymphoma cell lines. Serum IL-31 levels were low but differed between groups with no or strong pruritus. Expression of IL-31 was detectable at low levels in cell lines, but not in the tumor cells of SS patients. Stimulation with PMA/ionomycin led to indiscriminate expression in peripheral blood tumor cells and control T-cells. IL-2-stimulation resulted in expression only in 9/11 patient samples. IL-31Rα-expression was detectable in 10/10 cell lines, 8/15 peripheral blood samples from SS patients, and 4/10 controls; whereas, OSMRβ mRNA was detectable in 4/10 cell lines, but only one patient and control sample. The results of our analyses regarding serum levels and receptor expression do not suggest a central role of IL-31 in MF/SS pathogenesis. However, the results of IL-2 stimulation as well as the increased IL-31 levels in patients with strong pruritus offer a rationale for therapeutic approach in this subset of patients.
Similar content being viewed by others
References
Abraham RM, Zhang Q, Odum N, Wasik MA (2011) The role of cytokine signaling in the pathogenesis of cutaneous T-cell lymphoma. Cancer Biol Ther 12:1019–1022
Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S et al (2010) Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 28:4730–4739
Al-Yacoub N, Fecker LF, Möbs M, Plötz M, Braun FK, Sterry W et al (2012) Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling. J Invest Dermatol 132:2263–2274
Bilsborough J, Leung DY, Maurer M, Howell M, Boguniewicz M, Yao L 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 117:418–425
Chang TP, Vancurova I (2013) NFκB function and regulation in cutaneous T-cell lymphoma. Am J Cancer Res 3:433–445
Demierre MF, Gan S, Jones J, Miller DR (2006) Significant impact of cutaneous T-cell lymphoma on patients’ quality of life: results of a 2005 National Cutaneous Lymphoma Foundation Survey. Cancer 107:2504–2511
Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR et al (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5:752–760
Diveu C, Lelièvre E, Perret D, Lak-Hal AH, Froger J, Guillet C et al (2003) GPL, a novel cytokine receptor related to GP130 and leukemia inhibitory factor receptor. J Biol Chem 278:49850–49859
Dreuw A, Radtke S, Pflanz S, Lippok BE, Heinrich PC, Hermanns HM (2004) Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J Biol Chem 279:36112–36120
Hawro T, Saluja R, Weller K, Altrichter S, Metz M, Maurer M (2014) Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy 69:113–117
Hwang ST, Janik JE, Jaffe ES, Wilson WH (2008) Mycosis fungoides and Sézary syndrome. Lancet 371:945–957
Imam MH, Shenoy PJ, Flowers CR, Phillips A, Lechowicz MJ (2013) Incidence and survival patterns of cutaneous T-cell lymphomas in the United States. Leuk Lymphoma 54:752–759
Joehanes R, Nelson JC (2008) QGene 4.0, an extensible Java QTL-analysis platform. Bioinformatics 24:2788–2789
Laharanne E, Oumouhou N, Bonnet F, Carlotti M, Gentil C, Chevret E et al (2010) Genome-wide analysis of cutaneous T-cell lymphomas identifies three clinically relevant classes. J Invest Dermatol 130:1707–1718
Larsen CS (1990) Activation of human T lymphocytes by phorbol-12,13-dibutyrate and ionomycin. Scand J Immunol 31:353–360
Mao X, Orchard G, Mitchell TJ, Oyama N, Russell-Jones R, Vermeer MH et al (2008) A genomic and expression study of AP-1 in primary cutaneous T-cell lymphoma: evidence for dysregulated expression of JUNB and JUND in MF and SS. J Cutan Pathol 35:899–910
Marti RM, Wasik MA, Kadin ME (1996) Constitutive secretion of GM-CSF by three different cell lines derived from a single patient with a progressive cutaneous lymphoproliferative disorder. Cytokine 8:323–329
Miyagaki T, Sugaya M, Suga H, Ohmatsu H, Fujita H, Asano Y et al (2013) Increased CCL18 expression in patients with cutaneous T-cell lymphoma: association with disease severity and prognosis. J Eur Acad Dermatol Venereol 27:e60–e67
Nobbe S, Dziunycz P, Mühleisen B, Bilsborough J, Dillon SR, French LE, Hofbauer GF (2012) IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. Acta Derm Venereol 92:24–28
Ohmatsu H, Sugaya M, Suga H, Morimura S, Miyagaki T, Kai H et al (2012) Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol 92:282–283
Papadavid E, Economidou J, Psarra A, Kapsimali V, Mantzana V, Antoniou C et al (2003) The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sézary syndrome. Br J Dermatol 148:709–718
Perrigoue JG, Li J, Zaph C, Goldschmidt M, Scott P, de Sauvage FJ (2007) IL-31-IL-31R interactions negatively regulate type 2 inflammation in the lung. J Exp Med 204:481–487
Ralfkiaer E (1991) Immunohistological markers for the diagnosis of cutaneous lymphomas. Semin Diagnost Pathol 8:62–72
Siakantari M (2010) Classification and molecular pathogenesis of CTCL. Melanoma Res 20:20–21
Singer EM, Shin DB, Nattkemper LA, Benoit BM, Klein RS, Didigu CA 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 133:2783–2785
Siniewicz-Luzeńczyk K, Stańczyk-Przyłuska A, Zeman K (2013) Correlation between serum interleukin-31 level and the severity of disease in children with atopic dermatitis. Postepy Dermatol Alergol 30:282–285
Steininger A, Möbs M, Ullmann R, Köchert K, Kreher S, Lamprecht B et al (2011) Genomic loss of the putative tumor suppressor gene E2A in human lymphoma. J Exp Med 208:1585–1593
Szegedi K, Kremer AE, Kezic S, Teunissen MB, Bos JD, Luiten RM et al (2012) Increased frequencies of IL-31-producing T cells are found in chronic atopic dermatitis skin. Exp Dermatol 21:431–436
Vij A, Duvic M (2012) Prevalence and severity of pruritus in cutaneous T cell lymphoma. Int J Dermatol 51:930–934
Vowels BR, Lessin SR, Cassin M, Jaworsky C, Benoit B, Wolfe JT, Rook AH (1994) Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol 103:669–673
Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al (2005) WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768–3785
Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S et al (1997) EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354–371
Zhang C, Li B, Gaikwad AS, Haridas V, Xu Z, Gutterman JU, Duvic M (2008) Avicin D selectively induces apoptosis and downregulates p-STAT-3, bcl-2, and survivin in cutaneous T-cell lymphoma cells. J Invest Dermatol 128:2728–2735
Zhang C, Li B, Zhang X, Hazarika P, Aggarwal BB, Duvic M (2010) Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients’ PBMCs: potential role for STAT-3 and NF-kappaB signaling. J Invest Dermatol 130:2110–2119
Zhang Q, Putheti P, Zhou Q, Liu Q, Gao W (2008) Structures and biological functions of IL-31 and IL-31 receptors. Cytokine Growth Factor Rev 19:347–356
Conflict of interest
All authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
M. Möbs and S. Gryzik contributed equally as primary investigators.
Rights and permissions
About this article
Cite this article
Möbs, M., Gryzik, S., Haidar, A. et al. Analysis of the IL-31 pathway in Mycosis fungoides and Sézary syndrome. Arch Dermatol Res 307, 479–485 (2015). https://doi.org/10.1007/s00403-014-1527-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-014-1527-x