Correction

Article Outline

• Copyright

The following correction applies to the Molecular mechanisms in allergy and clinical immunology article by Dinarello entitled “IL-18: A T_H1-inducing, proinflammatory cytokine and new member of the IL-1 family,” which appeared in volume 103, number 1, part 1, p 11-24, of the Journal.

Formerly called IFN-γ–inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the T_H1 response, primarily by its ability to induce IFN-γ production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-γ production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1β share significant primary amino acid sequences and are similarly folded as all-β pleated sheet molecules. Also similar to IL-1β, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1β precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1β–converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as T_H1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Rα, a member of the IL-lR family previously identified as the IL-1R–related protein (IL-1Rrp), and a signaling chain, the IL-18Rβ, also a member of the IL-1R family. The IL-18R complex recruits IL-1R–activating kinase and TNF receptor–associated factor-6, which phosphorylates nuclear factor κB (NFκB)–inducing kinase with subsequent activation of NFκB. A secreted IL-18 binding protein also exists, which functions as a natural inhibitor of IL-18 activity. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity. (J Allergy Clin Immunol 1999;103:11-24.)

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 2. 

  Model for IL-18 signal transduction. IL-18 binds to the IL-18Rα chain³⁶ (also known as IL-1Rrp¹) and recruits the IL-18Rβ chain³⁶ (also known as AcPL³⁸). This heterodimeric complex recruits MyD88 and IRAK. Phosphorylated IRAK activates TRAF-6, and in turn NIK is phosphorylated. This results in activation of IKK and then phosphorylation of IκB. Phosphorylated IκB degrades and releases the p50 and p65 components of NFκB. Free NFκB migrates through nuclear pores and translocates to nuclear DNA for gene transcription. Adapted from J Leukoc Biol 1998;63:650-7.

Key words: Cytokines, inflammation, IFN-γ