Unique Action of Interleukin-18 on T Cells and Other Immune Cells

Abstract

Interleukin (IL)-18 was originally discovered as a factor that enhances interferon (IFN)-γ production by anti-CD3-stimulated Th1 cells, particularly in association with IL-12. IL-12 is a cytokine that induces development of Th1 cells. IL-18 cannot induce Th1 cell development, but has the capacity to activate established Th1 cells to produce IFN-γ in the presence of IL-12. Thus, IL-18 is regarded as a proinflammatory cytokine that facilitates type 1 responses. However, in the absence of IL-12 but presence of IL-2, IL-18 stimulates natural killer cells, NKT cells, and even established Th1 cells to produce IL-3, IL-9, and IL-13. Thus, IL-18 also facilitates type 2 responses. This unique function of IL-18 contributes to infection-associated allergic diseases. Together with IL-3, IL-18 stimulates mast cells and basophils to produce IL-4, IL-13, and chemical mediators such as histamine. Thus, IL-18 also induces innate-type allergic inflammation. IL-18 belongs to the IL-1 family of cytokines, which share similar molecular structures, receptors structures, and signal transduction pathways. Nevertheless, IL-18 shows a unique function by binding to a specific receptor expressed on distinct types of cells. In this review article, I will focus on the unique features of IL-18 in lymphocytes, basophils, and mast cells, particularly in comparison with IL-33.

Keywords: ILC2; Th1; innate-type allergy; interferon-γ; interleukin-18; interleukin-33; interleukin-4.

Figure 1

A proposal model for lipopolysaccharide (LPS)-induced liver injury in Propionibacterium acnes (P. acnes)-primed and LPS-challenged mice. Wild-type mice or mice deficient for interleukin (IL)-18, MyD88, or TRIF were administered with heat-killed P. acnes and examined for their hepatic granuloma formation at day 7 after this treatment. Only P. acnes-primed MyD88 did not develop hepatic granuloma at day 7 after treatment, suggesting that P. acnes treatment induces hepatic granuloma in a MyD88-dependent manner, but TRIF-independent manner. Although TRIF-deficient mice normally developed hepatic granulomas after P. acnes treatment, they could not release IL-18 or develop liver injury, suggesting that LPS TRIF-dependently activated caspase-1 via NLRP3 inflammasome. And, resultant IL-18 induces liver injury by induction of interferon-γ, FasL, and tumor necrosis factor-α.

Figure 2

Interleukin (IL)-18 facilitates both Th1 response and Th2 response. In combination with IL-12, IL-18 stimulates Th1 cells, natural killer (NK) cells, and NKT cells to produce robust interferon (IFN)-γ, resulting in the clearance of intracellular microbes. However, without IL-12, but with IL-2, IL-18 induces Th1 cells, NK cells, and NKT cells to produce IL-13 and IFN-γ both of which are involved in host defense response or in infection-associated allergy. NKT cells stimulated with IL-2 and IL-18 express CD40L and produce IL-4, thereby inducing B cells to produce IgE.

Figure 3

Interleukin (IL)-18 and IL-33 induce innate allergic response by stimulation of mast cells and basophils. Like mast cells or basophils stimulated with Ag/IgE complex, mast cells and basophils, expressing IL-18R and IL-33R, produce IL-4, IL-13 and chemical mediators, after being stimulated with IL-18 and IL-33, respectively.

Figure 4

Induction of bronchial asthma by intranasal administration of interleukin (IL)-18 or IL-33. As natural killer (NK)T cells constitutively express IL-18R, intranasal administration of IL-18 into wild-type mice, but not into Rag2Ko mice induced bronchial asthma by induction of IL-4 and IL-13 from NKT cells. In contrast, intranasal administration of IL-33 into wild-type mice and Rag2Ko mice equally induce bronchial asthma, because Rag2Ko mice are equipped with ILC2 which express IL-33R and produce IL-13 in response to IL-33.