Serum IL-31 levels are increased in a subset of patients with mastocytosis and correlate with disease severity in adult patients

Hartmann, Karin; Wagner, Nicola; Rabenhorst, Anja; Pflanz, Liselotte; Leja, Silke; Förster, Anja; Gehring, Manuela; Kapp, Alexander; Raap, Ulrike

doi:10.1016/j.jaci.2012.11.008

Cited by 61 publications

(62 citation statements)

References 8 publications

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“…IL-6 induced a similar transcriptional induction of DJ-1 in LAD2 cells pre-stimulated with SCF for 48h (S3A Fig). This was in contrast to two other biomarkers associated with elevated tryptase levels in mastocytosis, IL-31 and histamine [23, 45–47], which had no effect on DJ-1 expression (S3B and S3C Fig). …”

Section: Resultsmentioning

confidence: 56%

“…To understand the basis for this unexpected elevation, we examined whether biomarkers known to be associated with high mast cell burden [22, 23, 44–47] could increase DJ-1 expression, thus counteracting the increased turnover of DJ-1 by constitutive KIT activation. IL-6 was of interest because serum IL-6 levels in mastocytosis correlate with tryptase and elevated IL-6 is a better predictor than other cytokines for disease progression [23].…”

Section: Resultsmentioning

confidence: 99%

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Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

et al. 2016

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Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage.

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

et al. 2016

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“…This may be caused by a small group of patients in stage IV in our study. In other dermatological diseases, correlation of IL-31 with disease activity has been shown in AD (40)(41)(42)(43)(44) and mastocytosis (51). This correlation has not been found in patients with psoriasis (39).…”

Section: Discussionmentioning

confidence: 98%

Il-31 Does not Correlate to Pruritus Related to Early Stage Cutaneous T-cell Lymphomas but is Involved in Pathogenesis of the Disease

Malek¹,

Gleń²,

Rębała³

et al. 2015

Acta Derm Venerol

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Mycosis fungoides (MF) and Sézary syndrome (SS) belong to the group of primary cutaneous T-cell lymphomas (CTCL). Regardless of the stage of the disease, patients with MF and SS can suffer from chronic pruritus. The aim of the study was to investigate the correlation between the interleukin 31 (IL-31) serum level, the degree of pruritus and CTCL severity; and to compare the frequency of IL-31 gene polymorphisms between patients and the control group, and between patients at different stages of the disease. Pruritus affected 67.7% of patients with MF and SS in our study. The IL-31 serum level was significantly higher in CTCL patients than in the control group but there were no positive correlation between IL-31 serum level and pruritus. A statistically significant difference in allele frequencies for IL-31 IVS2+12 gene polymorphisms between early and advanced stages was detected; GAG haplotype was more frequent and AGA was less frequent in stage IA patients compared with patients in the other stages of the disease.

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“…Thus, IL-31 appears to exert bifunctional effects, with low doses promoting the antimicrobial barrier but high doses additionally impairing the physical barrier. Low levels of IL-31 may be produced by different skin-resident immune cells, whereas high levels are associated with different inflammatory skin diseases, including AD, allergic contact dermatitis, and prurigo nodularis (30), but also with tumors such as mastocytosis and cutaneous T cell lymphoma (42)(43)(44)(45), and with pruritus in many pathological conditions (46)(47)(48)(49). Thus, these findings suggest that IL-31 is an emerging therapeutic target.…”

mentioning

confidence: 99%

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Hänel

Pfaff

Cornelissen

et al. 2016

The Journal of Immunology

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Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31–dependent gene expression was determined in three-dimensional organotypic skin models. IL-31–regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.

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Serum IL-31 levels are increased in a subset of patients with mastocytosis and correlate with disease severity in adult patients

Cited by 61 publications

References 8 publications

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Il-31 Does not Correlate to Pruritus Related to Early Stage Cutaneous T-cell Lymphomas but is Involved in Pathogenesis of the Disease

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

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