The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment

Elisa Ferretti, Anna Corcione, Vito Pistoia

Research output: Contribution to journalReview article

Abstract

IL-31 is a recently identified cytokine with a well-defined role in the pathogenesis of pruritus. IL-31, whose production is induced by IL-4 and IL-33, binds a heterodimeric receptor (R) composed of the exclusive IL-31RA chain and the shared oncostatin M R. Signaling through the IL-31R involves the MAPK, PI3K/AKT and Jak/STAT pathways. Different variants and isoforms of IL-31RA with different signaling activities have been identified. IL-31 is produced predominantly by circulating Th2 lymphocytes and skin-homing CLA+CD45RO+ T cells. Studies in humans have demonstrated a pathogenic role for IL-31 in atopic dermatitis and allergic asthma. The first demonstration of the involvement of the IL-31/IL-31R axis in cancer came from studies in patients with mycosis fungoides/Sézary syndrome, the most frequent, cutaneous T cell lymphoma. Tumor cells were shown to produce IL-31, whose serum levels correlated with pruritus intensity. Follicular lymphoma (FL) B cells and their counterparts-germinal center B cells-produced IL-31 and expressed IL-31R, which signaled in the former, but not the latter, cells. IL-31 released in association with microvesicles promoted tumor growth through autocrine/paracrine loops. Malignant mast cells from patients with mastocytosis or Philadelphia-negative myeloproliferative disorder produced IL-31, which contributed to pruritus pathogenesis. Finally, patients with endometrial carcinoma displayed high serum levels of IL-31 and IL-33, which may represent promising disease biomarkers. Targeting strategies for the IL-31/IL-31R axis have been developed, including the CIMM331 humanized anti-human IL-31RA antibody recently tested in a phase I/Ib study.

Original languageEnglish
Pages (from-to)711-717
Number of pages7
JournalJournal of Leukocyte Biology
Volume102
Issue number3
DOIs
Publication statusPublished - Sep 2017

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Keywords

  • Animals
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neoplasm
  • B-Lymphocytes
  • Extracellular Signal-Regulated MAP Kinases
  • Humans
  • Interleukins
  • Janus Kinases
  • MAP Kinase Signaling System
  • Neoplasms
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptors, Interleukin
  • STAT Transcription Factors
  • Tumor Microenvironment
  • Journal Article
  • Review

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