Defective NK Cell Activity and Th1 Response in IL-18–Deficient Mice

Takeda, Kiyoshi; Tsutsui, Hiroko; Yoshimoto, Tomohiro; Adachi, Osamu; Yoshida, Nobuaki; Kishimoto, Tadamitsu; Okamura, Haruki; Nakanishi, Kenji; Akira, Shizuo

doi:10.1016/s1074-7613(00)80543-9

Cited by 841 publications

(676 citation statements)

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“…Mice deficient in IL-18 suffer from impaired IFN-g production and MF derived from these animals fail to promote Th1 responses in vitro [21]. Accordingly, IL-18 is involved in protective immunity against a broad range of intracellular pathogens including Leishmania, Toxoplasma, and Salmonella [19].…”

Section: Discussionmentioning

confidence: 99%

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MU. IFN-c secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MU to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MU. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophildriven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.Key words: IFN-c . IL-18 . Mouse . Neutrophils . Tuberculosis IntroductionDespite more than 125 years of research and development, tuberculosis (TB) remains the most hazardous bacterial infection worldwide with approximately 2 million people dying of the disease annually [1]. The risk of disease is increased by immunocompromising conditions such as AIDS emphasizing that T-cell immunity protects latently infected individuals against active TB. The innate immune response to Mycobacterium tuberculosis instructs acquired immunity in the initial stage, and executes effector mechanisms in the chronic stage.M. tuberculosis is usually transmitted via aerosols and establishes stable infection in the lung. There, M. tuberculosis is engulfed by MF and DC, which serve as host cells for mycobacterial survival and propagation. Binding of mycobacterial ligands to TLR-2, -4 and -9 promotes release of chemokines and proinflammatory cytokines, expression of adhesion molecules and attraction of MF, DC and PMN. Two crucial MF-and DCderived cytokines, , induce NK-cell activity and bias immunity towards a Th1 cell response characterized by profound 396IFN-g production, which is considered critical for protection against M. tuberculosis [2]. Activated MF express anti-mycobacterial molecules such as nitric oxide synthase (NOS)-2 (also known as inducible NOS) and LRG47 as well as cytokines such as TNF-a, which promotes granuloma formation within the infected tissue to sequester the bacilli from dissemination [2].Despite the prevailing assumption that resistance to M. tuberculosis infection depends on microbe sensing through TLR, their importance for mounting a protective immune response against M. tuberculosis remains controversial. While some groups found that TLR-mediated...

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Section: Discussionmentioning

confidence: 99%

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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“…IL-18 may mediate its effects directly by augmentation of IFN-γ production 6 10 23 24 or by enhancement of the expression of the IL-12R complex, thereby potentiating the effects of IL-12 25. While many studies have focused attention on the regulation of the IL-12R during Th cell differentiation, fewer have focused on regulation of the IL-18R 24 26 27 28 29.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, IL-18 has been regarded as a proinflammatory cytokine that can synergize with IL-12 to increase IFN-γ production, NK cell cytotoxicity, and Th1 responses 2 3 4 5. While IL-18 clearly enhances Th1 responses, it is less clear whether IL-18 is capable of initiating Th1 differentiation in the absence of IL-12 6 7 8 9 10. Although a majority of published reports link IL-18 with Th1-associated functions, IL-18 has recently been shown to augment Th2 responses 11 12 13 14.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

Smeltz

Chen

Hu‐Li

et al. 2001

The Journal of Experimental Medicine

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Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)-γ production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor α chain (IL-18Rα) expression. The majority of peripheral CD4+ T cells constitutively expressed the IL-18Rα. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Rα expression was observed. IL-12–mediated upregulation of IL-18Rα required IFN-γ. Activated CD4+ T cells that expressed low levels of IL-18Rα could produce IFN-γ when stimulated with the combination of IL-12 and IL-18, while CD4+ cells which expressed high levels of IL-18Rα could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Rα expression. Both IL-4−/− and signal transducer and activator of transcription (Stat)6−/− T cells expressed higher levels of IL-18Rα after TCR stimulation. Furthermore, activated T cells from Stat6−/− mice produced more IFN-γ in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Rα by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

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“…[1][2][3][4][5][6] This molecule is able to induce IFN-␥ and TNF-␣ production by T cells 5,6 and to stimulate NK cell cytotoxicity 7 and T-cell proliferation. 8,9 IL-18, like IL-1␤, is synthesized as an inactive precursor (pro-IL-18 24kDa), which is cleaved by interleukin-1␤-converting enzyme (ICE or caspase-1) into an active 18 KDa mature form and secreted.…”

mentioning

confidence: 99%