Abstract:
:IL-1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL-36α, IL-36β and IL-36γ, which belong to the extended IL-1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL-36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL-36 receptor antagonist result in a severe form of psoriasis. IL-36 family cytokines are initially expressed as inactive precursors that require proteolytic processing for activation. The neutrophil granule-derived protease elastase proteolytically processes and activates IL-36α and IL-36γ, increasing their biological activity ~ 500-fold, and also robustly activates IL-1α and IL-33 through limited proteolytic processing. Consequently, inhibitors of elastase activity may have potential as anti-inflammatory agents through antagonizing the activation of multiple IL-1 family cytokines. Using in silico screening approaches, we have identified small-molecule inhibitors of elastase that can antagonize activation of IL-36γ by the latter protease. The compounds reported herein may have utility as lead compounds for the development of inhibitors of elastase-mediated activation of IL-36 and other IL-1 family cytokines in inflammatory conditions, such as psoriasis.
journal_name
FEBS Open Biojournal_title
FEBS open bioauthors
Sullivan GP,Davidovich PB,Sura-Trueba S,Belotcerkovskaya E,Henry CM,Clancy DM,Zinoveva A,Mametnabiev T,Garabadzhiu AV,Martin SJdoi
10.1002/2211-5463.12406subject
Has Abstractpub_date
2018-03-25 00:00:00pages
751-763issue
5issn
2211-5463pii
FEB412406journal_volume
8pub_type
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