Dataset Information

Unprocessed Interleukin-36? Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1.

ABSTRACT: Generalized pustular psoriasis is a severe skin disease characterized by epidermal hyperplasia, neutrophil-rich abscesses within the epidermis, and a mixed inflammatory infiltrate in the dermis. The disease may be caused by missense mutations in the IL-36 receptor antagonist, IL-36Ra. Curiously, the related IL-1Ra has therapeutic effects in some of these latter patients. Here, using an experimental mouse model of psoriasiform skin inflammation, we demonstrate in vivo connections between IL-36 and IL-1 expression. After disease initiation, IL-36?-deficient mice exhibited dramatically diminished skin pathology, including absence of epidermal neutrophils, reduced keratinocyte acanthosis, and less dermal edema. In contrast, IL-36? and IL-36? knockout mice developed disease indistinguishable from that of wild-type mice. The endogenous IL-36? was not processed through proteolysis. Although IL-36? expression was strongly induced in an IL-1 signaling-dependent manner during disease, expression of IL-1? was also dependent upon IL-36?. Hence, after being upregulated by IL-1?, IL-36? acts through a feedback mechanism to boost IL-1? levels. Analyses of double knockout mice further revealed that IL-36? and IL-1? cooperate to promote psoriasis-like disease. In conclusion, IL-1? and IL-36? form a self-amplifying inflammatory loop in vivo that in patients with insufficient counter regulatory mechanisms may become hyper-engaged and/or chronic.

SUBMITTER: Milora KA

PROVIDER: S-EPMC4648684 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Unprocessed Interleukin-36α Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1.

Milora Katelynn A KA Fu Hangfei H Dubaz Ornella O Jensen Liselotte E LE

The Journal of investigative dermatology 20150723 12

Generalized pustular psoriasis is a severe skin disease characterized by epidermal hyperplasia, neutrophil-rich abscesses within the epidermis, and a mixed inflammatory infiltrate in the dermis. The disease may be caused by missense mutations in the IL-36 receptor antagonist, IL-36Ra. Curiously, the related IL-1Ra has therapeutic effects in some of these latter patients. Here, using an experimental mouse model of psoriasiform skin inflammation, we demonstrate in vivo connections between IL-36 an ...[more]

PMID: 26203636

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Project description:Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROS-mediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1-4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in the cytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein-protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

Project description:BackgroundThe polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to down regulate NF-κB; an important contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the effects.MethodsThe study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting.ResultsImiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways. Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis.ConclusionsResveratrol ameliorates psoriasis, and changes expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner, which suggests resveratrol, might have a role in the treatment of psoriasis and should be explored further in a human setting.

Dataset Information

Unprocessed Interleukin-36? Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1.

Publications

Unprocessed Interleukin-36α Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1.

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