Figure 1.

Interleukin (IL)-37 maintains its anti-inflammatory outcomes by limiting IL-18Rα from adhering to IL-18 and by attracting the orphan decoy IL-1R8 to the IL-18R/IL-37/IL-1R8 complex. This prevents IL-18Rα from participating in the transduction of pro-inflammatory IL-18 signals via the myeloid differentiation primary response 88 (MyD88) pathway and NF-κB. Focal adhesion kinase (FAK), signal transducer and activator of transcription (STAT)1, STAT3, mammalian target of rapamycin (mTOR), p53, p38, paxillin, spleen tyrosine kinase (Syk), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP-2), and protein kinase B (AKT) are pro-inflammatory signal-transducing mediators whose activation is reduced by IL-37, whereas protein phosphatase and tensin homolog (PTEN), which inhibits the PK3 kinase, FAK, mTOR, and mitogen-activated protein kinase (MAPK) pathways is enhanced by IL-37. mTOR has a pro-inflammatory function as it blocks IL-10 and promotes IL-12, as well as an anti-inflammatory function as IL-6 is blocked by rapamycin. MAPK regulates the production of pro-inflammatory cytokines such as IL-6 and tumour necrosis factor (TNF)-α. After activation of NLRP3, there is a subsequent formulation of the NLRP3 inflammasome that cleaves, for instance, pro-inflammatory IL-18 to its active form. Inhibition of Fyn dampens the systemic inflammation and Fyn is engaged in pro-inflammatory stimuli, for instance by stimulating the production of IL-6 and TNF-α. NF-κB is central in the regulation of inflammatory processes and stimulates the production of many pro-inflammatory cytokines including IL-1, IL-12, IL-18, and chemokines such as CXCL10. PTEN negatively regulates the expression of pro-inflammatory cytokines such as IL-1, IL-6, and TNF- α. Mer decreases the levels of CCL1 and IL-6. AMPK as well as STAT6, which is activated by IL-4 and IL-13, inhibit the NF-κB signalling pathway. STAT3 can lead to transcriptional activation of genes encoding pro-inflammatory cytokines including IL-6, IL-17, and IL-23.