Identification of small-molecule elastase inhibitors as antagonists of IL-36 cytokine activation.

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-36?, IL-36? and IL-36?, which belong to the extended IL-1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL-36? 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-36? and IL-36?, increasing their biological activity ~ 500-fold, and also robustly activates IL-1? 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-36? 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.

SUBMITTER: Sullivan GP 

PROVIDER: S-EPMC5929933 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature