The Pathogenetic Role of IL-1β in Severe Epidermolysis Bullosa Simplex

Wally, Verena; Lettner, Thomas; Peking, Patricia; Peckl-Schmid, Doris; Murauer, Eva M.; Hainzl, Stefan; Hintner, Helmut; Bauer, Johann

doi:10.1038/jid.2013.31

Cited by 41 publications

(58 citation statements)

References 11 publications

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“…In EB, The skin pathological phenotype of EB is caused by inflammation and by minor trauma as previous demonstrated [23], [24]. The IL-1β signaling is constitutively activated in EB keratinocytes [25], and the serum IL-1α and IL-1β levels are several-fold increased even in the mild type of EB [26]. Sustained skin disruption in EB patients can lead to aberrant skin secretion with high circulating level of IL-1 that may potentially cause emaciation, vascular disorder, systemic amyloidosis and other visceral pathologies.…”

Section: Discussionmentioning

confidence: 73%

Persistent Release of IL-1s from Skin Is Associated with Systemic Cardio-Vascular Disease, Emaciation and Systemic Amyloidosis: The Potential of Anti-IL-1 Therapy for Systemic Inflammatory Diseases

et al. 2014

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The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.

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Section: Discussionmentioning

confidence: 73%

Persistent Release of IL-1s from Skin Is Associated with Systemic Cardio-Vascular Disease, Emaciation and Systemic Amyloidosis: The Potential of Anti-IL-1 Therapy for Systemic Inflammatory Diseases

et al. 2014

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“…In vitro studies on EBS-DM keratinocytes showed a significant upregulation of interleukin-1beta (IL-1ß), resulting in the activation of the c-jun N-terminal-kinase (JNK) stress pathway and subsequently in the overexpression of K14 and IL-1ß in a positive feedback loop. When impairing IL-1ß signaling, using anti-IL-1ß antibody or the small molecule diacerein, levels of IL-1ß, JNK and K14 decreased and the IF network was stabilized [3]. Based on this information, we launched a double-blinded, randomized, placebo-controlled pilot study using a 1% diacerein in the commonly used care cream ultraphil® as intervening agent, and ultraphil® alone as placebo.…”

Section: Resultsmentioning

confidence: 99%

Topical diacerein for epidermolysis bullosa: a randomized controlled pilot study

Wally

Kitzmueller

Lagler

et al. 2013

Orphanet Journal of Rare Diseases

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Blistering in epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is associated with an inflammatory phenotype, which can be disrupted by diacerein in vitro. In this pilot study we hypothesized, that a topical formulation of diacerein 1% reduces blistering. Five patients initially applied diacerein underneath both armpits. Then, each participant received 1% diacerein-cream for one armpit, and placebo for the other (randomized withdrawal). The number of blisters was reduced significantly (left: -78%; right: -66% of baseline) within two weeks and remained significantly below the initial level even during withdrawal in four patients. These findings point to a relevant effect of diacerein and provide important information for a confirmative study.

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“…Wally et al . found that the keratinocytes of patients with the Dowling–Meara subtype of EBS have constitutively activated IL‐1β signalling . Glial IL‐1β and tumour necrosis factor‐α can cause a central sensation of pain, but it is not yet known whether these cytokines activate pruriceptive neurons …”

Section: Discussionmentioning

confidence: 99%