Proteolytic Processing of Interleukin-1 Family Cytokines: Variations on a Common Theme

Abstract

Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease.

Current concepts of severe asthma

“…Many of these clusters are associated with high eosinophilia, and type 2 cytokine-directed therapies in specific subgroups have shown promise (Table 2) (32-34, 47,[49][50][51][52][53][54][55][56][57][58][59][60][61][62]. In multiple studies, anti-IL-5 or anti-IL-5R therapy in patients with blood or sputum eosinophilia resulted in decreased exacerbations, lower daily oral CS dose, and, in some instances, improved symptoms and lung function (51, 53, 55, 57, 63), con- truncated cytokines with enhanced biological activities, although the exact cellular source of these cytokines in severe asthma is currently unclear (77). It is interesting to consider the possibility that in some patients, allergens and other environmental agents with protease activity induce low or no type 2 sensitization that would result in Th2 skewing and increased IgE levels, but instead promote the production of TSLP, IL-25, IL-33, or PGD2, which induce type 2 cytokine production in ILC2s.…”

Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin

“…They are emerging as major regulators of a variety of biological processes in the context of tissue development and homeostasis owing to their involvement in the activation of hormones, growth factors and cytokines, the activation and ectodomain shedding of signaling receptors and adhesion molecules, regulation of ion fluxes and extracellular matrix remodeling (Afonina et al, 2015;Chin et al, 2008;Naldini et al, 1992;Picard et al, 2008;Scudamore et al, 1998;Shimomura et al, 1993;Vallet et al, 1997;Wang et al, 1994;Yan et al, 2000).…”

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

“…3e and Supplementary Fig. S3a) 25,[34][35][36]53 . Together, these observations suggest that IL-36 and its processing factors are likely to be important in psoriasis.…”

“…New results describe neutrophil-derived proteases as well as cathespsin S, a lysosomal protease, as IL-36 cytokine processing enzymes 25,34,36 . In both situations the cleavage and activation of IL-36 appears to occur extracellularly, unlike other IL-1 family members that are primarily processed intracellularly, prior to secretion by non-conventional mechanisms 53 . We confirmed the ability of neutrophil-derived proteases, including elastase, to activate IL-36γ ( Supplementary Fig.…”