Journal
SCIENCE IMMUNOLOGY
Volume 7, Issue 78, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.ade5728
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Funding
- Irish Research Council Advanced Laureate program [IRCLA/2019/133]
- European Research Council Advanced Grant program [101020534]
- Science Foundation Ireland [14/IA/2622, 12/1A/1421, 19/FFP/6484]
- National Children's Research Center project [C/18/8]
- Slovene Research Agency [P1-0140]
- European Research Council (ERC) [101020534] Funding Source: European Research Council (ERC)
- Science Foundation Ireland (SFI) [14/IA/2622] Funding Source: Science Foundation Ireland (SFI)
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IL-37, a member of the IL-1 family, can be activated and exhibit proinflammatory effects upon processing by specific proteases. This finding is consistent with other IL-1 family members.
Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL- 37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, herewe showthat the longest IL-37 isoform, IL37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1 ss. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53truncated form of IL-37, mimicking the cathepsin S- processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R-/- animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases.
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