PMC

(A) IL-18 binds to IL-18Rα and recruits IL-18Rβ. The TIR domains of the two receptor chains approximate and MyD88 binds to the TIR domains and a strong proinflammatory IL-18-driven signal follows. (B) IL-37 binds to the IL-18Rα but recruits IL-1R8 instead of IL-18Rβ. MyD88 is recruited to the TIRb domain of IL-1R8 rather than to the TIR domain of IL-18Rα. The unique amino acids of the TIRb domain of IL-1R8 functions as a sink for MyD88; as a result, there is a weak or no signal []. The sequestering of MyD88 also prevents its participation in IL-1 and IL-18 receptor signaling. There is a similar sequestration of MyD88 by IL-1R8 for TLR signaling [].

The data are derived from human THP-1 cells transfected with IL-37b and stimulated with LPS plus IFNγ []. The horizontal line represents the level of mTOR and AMPK on a phosphokinase blot following stimulation of the cells transfected with the control plasmid. The decrease in mTOR and the increase in AMPK levels take place in cells transfected with IL-37b. The decrease in mTOR and the increase in AMPK are a consistent finding in IL-37 transfected, in cells from IL37-tg mice and in WT cells treated with recombinant IL-37 [, , ].

The data are derived from studies in cells transfected with human IL-37b [], recombinant IL-37 added to cells [, ], transgenic mice expressing human IL-37 [, , , ] and WT mice treated with recombinant IL-37 [, , , , , -]. The broad arrows suggest the impact of suppression of inflammatory cytokines, transcription factors and signaling kinases as well as anti-inflammatory pathways on acquired immunity.

The 5 splice variants transcripts of the IL-37 gene are shown. Exons 4, 5, and 6 are shared with isoforms IL-37a, b and d. IL-37a contains an IL-1 family consensus sequence of IHD in exon 4 (green bar above exon 4 sequence); nine amino acids forward is the putative N-terminus at lysine 27. Recombinant IL-37a with an N-terminus at lysine 27 is active [, ]. Precursor IL-37b is the transcript expressed in IL-37tg mice. Nine amino acids forward from the IHD sequence in IL-37b is lysine 53 (red K). The biological activity of IL-37b with the N-terminus at lysine 53 is presently unknown. IL-37b with the N-terminus at valine 46 (red arrow) is found naturally [] and a recombinant form is highly active []. Exon 1 of IL-37b contains the caspase-1 cleavage site (blue D20). Another consensus sequence, LED (green bar above), is present in exon 1 of IL-37b and nine amino acids forward is a putative N-terminus at tryptophan 16, which is close to the caspase-1 cleavage site N-terminus at D20. Recombinant IL-37b with the N-terminus at D20 is biologically weak in binding to IL-18Rα []. The IL-37d transcript is similar to IL-37b sharing exons 1, 4, 5 and 6. IL-37c shares with IL-37b exons 1, 2, 5 and 6. The activity of recombinant IL-37c, d and e are presently unknown.

(A) Nuclear activity of IL-37. Following stimulation by IL-1 or TLR agonists in human blood monocytes, the IL-37 precursor is synthesized and concentrations of the cytokine increase intracellularly [, , ]. Stimulation also triggers the activation of caspase-1 and the carboxyl domain of IL-37 containing the nuclear localization sequence is found in the nucleus [, ]. In mouse macrophages lacking NLRP3 or ASC transfected with human IL-37 precursor, there is no suppression of LPS-induced IL-6 compared to transfected WT macrophages []. Intracellular IL-37 associates with phopho-Smad3 as demonstrated by immunoprecipitation and immunofluorescence []. Small molecule inhibitor of Smad3 prevents the suppression of cytokines by IL-37 in vitro []. Although the intracellular complex of Smad3 and IL-37 has been reported [], there is no direct evidence that the complex binds to DNA and inhibit gene transcription as the mechanism for reduced expression of inflammatory genes. (B) As intracellular IL-37 increases as shown in A, the IL-37 precursor is exported from the cell into the extracellular space by an unknown mechanism. Western blotting reveals the IL-37 precursor can exist as a dimer in the supernatants of LPS-stimulated human blood monocytes []. With the addition of ATP to induce the activation of caspase-1, mature IL-37 is found in the supernatants also. Stimulation of human monocyte dendritic cells with either anti-HLA-1, anti-CD94 or anti-ICAM-1 results is secretion of both the mature and precursor forms of IL-37 without the ATP trigger [].