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    The Role of Interleukin-10 Family Members in Inflammatory Skin Diseases. Understanding the mechanism of action of interferon lambda and interleukin-22 on human primary keratinocytes and dermal fibroblasts with a focus on healing responses in inflammatory skin diseases

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    PhD Thesis (4.483Mb)
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    Publication date
    2015
    Author
    Alase, Adewonuola A.
    Supervisor
    Wittmann, Miriam
    Tobin, Desmond J.
    Keyword
    Interferon lambda; Interleukin-22; Interferon stimulated genes; Keratinocytes; Inflammatory skin diseases; Fibroblasts; Inflammation; SOCS; MAPKs
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Centre for Skin Sciences, School of Medical Sciences, Faculty of Life Sciences
    Awarded
    2015
    
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    Abstract
    Cutaneous lupus erythematosus (CLE) is an autoimmune disease that resolves with or without permanent scars depending on the subtype. Interferons (IFNs), including the skin specific IFNλ mainly activate STAT1, which results in inflammation in CLE and may play a significant role in scar formation in chronic discoid CLE. IL-22 activates STAT3 and it is emerging as a mediator with significant impact on normal wound repair, epidermal hyperproliferation and prevention of fibrosis. This work focussed on understanding the regulation and functional impact of IL-22 and IFNλ on skin cells. The counter-regulatory effect of IL-22 on the activities of IFNλ was assessed through downstream interferon stimulated genes (ISGs) expression in healthy and CLE keratinocytes. Cell proliferation and gap closure were investigated in skin resident cells using cell trace dye and scratch assay. Dermal fibroblasts were assessed for the presence of IFNλR1 and IL-22R1, downstream activities of the receptors. Results showed that IL-22 accelerated “scratch” closure in keratinocytes while IFNλ caused a delay in closure. IL-22 significantly downregulated IFNλ-induced chemokines expression in healthy, but not CLE keratinocytes. Reduced IL-22R1 expression and “STAT3 signature genes” was observed in CLE keratinocytes. A key finding of this project is that dermal fibroblasts respond to both IFNλ and IL-22. This work shows that IL-22 can reduce the damaging effect of IFNs in inflamed skin and also identifies dermal fibroblasts as important cells in skin immune responses. In conclusion, IL-10 family members can have both beneficial and destructive effects on the skin organ depending on the micro milieu and cell-type involved. Manipulating the balance of IL-10 family members in the skin may offer new therapeutic approach for both psoriasis and CLE.
    URI
    http://hdl.handle.net/10454/14303
    Type
    Thesis
    Qualification name
    PhD
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