Recent Advances in Progresses and Prospects of IL-37 in Central Nervous System Diseases

Abstract

Interleukin-37 (IL-37) is an effective anti-inflammatory factor and acts through intracellular and extracellular pathways, inhibiting the effects of other inflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), thereby exerting powerful anti-inflammatory effects. In numerous recent studies, the anti-inflammatory effects of IL-37 have been described in many autoimmune diseases, colitis, and tumors. However, the current research on IL-37 in the field of the central nervous system (CNS) is not only less, but mainly for clinical research and little discussion of the mechanism. In this review, the role of IL-37 and its associated inflammatory factors in common CNS diseases are summarized, and their therapeutic potential in CNS diseases identified.

Keywords: Interleukin-37; anti-inflammatory; central nervous system diseases; cytokines; inflammatory.

Figure 1

Pathway through which Interleukin-37 (IL-37) exerts anti-inflammatory effects. In extracellular pathway, IL-37 binds with IL-18 receptor α chain (IL-18Rα) and IL-1 receptor 8 (IL-1R8) to form a trimeric complex. The trimeric complex activates adenosine 5′-monophosphate-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), STAT6 and phosphate and tension homology deleted on chromosome ten (PTEN), and inhibits the pathway of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK) and nuclear factor-κB (NF-κB). At the same time, PTEN inhibits the PI3K/AKT/mTOR pathway, thereby inhibiting the production of NF-κB and pro-inflammatory cytokines, including IL-6, tumor necrosis factor-α (TNF-α) and IL-1β. In intracellular pathway, pro-IL-37 is cleaved by caspase-1 to become IL-37. A part of IL-37 is released outside the cell, and a part binds to drosophila mothers against decapentaplegic 3 (Smad3) in the cytoplasm. After entering the nucleus, it inhibits the transcription of other inflammatory cytokines, such as IL-6 and TNF-α.