IL-18 Background
IL-18 is a proinflammatory cytokine that belongs to the IL-1 family of ligands. Macrophages and dendritic cells are the primary sources for active IL-18, but the IL-18 precursor is constitutively expressed in epithelial cells throughout the body. Similar to IL-1beta, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. But unlike IL-1beta, the IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The IL-18 receptors, although distinct from IL-1 receptors, also belong to the IL-1 receptor family. The IL-18 receptor (IL-18R) complex consists of two receptor chains; a ligand-binding chain termed the IL-18Ralpha chain and a co-receptor termed the IL-18Rbeta chain; both chains are required for signaling (Ref.1 and 2).
IL-18 Activity
The activity of IL-18 is balanced by the presence of a high affinity, naturally occurring IL-18 binding protein (IL-18BP). In humans, increased disease severity can be associated with an imbalance of IL-18 to IL-18BP, such that the levels of free IL-18 are elevated in the circulation (Ref.3). IL-18 activates PI3K/Akt and MEK/ERK1/2 signaling pathways, contributing to the production of the chemokine MCP-1, which plays an important role in the recruitment of leukocytes at inflammatory sites and subsequently the development of adaptive immunity (Ref.4). By binding to IL-18RA, IL-18 upregulates IL-1R-associated kinase (IRAK) and TNF receptor associated factor 6 (TRAF6). TRAF6 activates NF-kappaB-inducing kinase (NIK), which further phosphorylates and activates the I-kappa-B kinases (IKKs). IKKs eventually phosphorylate the IKB inhibitory subunit of IKB-nuclear factor kappa-B (NF-KB) complex. IKB is then polyubiquitinated, leading to its degradation by the proteasome causing nuclear translocation of free NF-KB dimers, ultimately ending in activation of pro-inflammatory cytokine genes. TRAFs may also regulate p38 mitogen activated protein kinase (p38 MAPK) as well as PI3K/AKT pathways (Ref.5). IL-18 has been implicated in several autoimmune diseases, myocardial function, emphysema, metabolic syndromes, psoriasis, inflammatory bowel disease, hemophagocytic syndromes, macrophage activation syndrome, sepsis, and acute kidney injury, although in some models of disease, IL-18 is protective (Ref.3).
References
1. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process.
Dinarello CA. Am J Clin
Nutr. 2006 Feb;83(2):447S-455S. Review.
2. Differences in signaling pathways by IL-1beta and IL-18.
Lee JK, Kim SH, Lewis EC, Azam T, Reznikov LL, Dinarello CA.
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8815-20. Epub 2004 May 25.
3.Interleukin-18 and IL-18 binding protein.
Dinarello CA, Novick D, Kim S, Kaplanski G.
Front Immunol. 2013 Oct 8;4:289. doi: 10.3389/fimmu.2013.00289. Review.
4.IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways.
Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW.
J Immunol. 2005 Dec 15;175(12):8280-6.
