A Role for IL-18 in Neutrophil Activation

Leung, Bernard P.; Culshaw, Shauna; Gracie, J. Alastair; Hunter, David J.; Canetti, Cláudio; Campbell, Carol; Cunha, Fernando Q.; Liew, Foo Y.; McInnes, Iain B.

doi:10.4049/jimmunol.167.5.2879

Cited by 273 publications

(260 citation statements)

References 44 publications

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“…1), in accordance with data previously shown for LPS and bacterial lipoproteins (20,42). IL-18Rs activate similar signaling pathways to TLRs, and are expressed on neutrophils (43). In keeping with this, we observed limited responses to IL-18 in our assays, but in comparison to IL-18, TLR signaling was considerably more efficacious in modulating cell surface adhesion molecule expression.…”

Section: Discussionsupporting

confidence: 79%

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

Sabroe

Prince

Jones

et al. 2003

The Journal of Immunology

305

290

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Neutrophil responses to commercial LPS, a dual Toll-like receptor (TLR)2 and TLR4 activator, are regulated by TLR expression, but are amplified by contaminating monocytes in routine cell preparations. Therefore, we investigated the individual roles of TLR2 and TLR4 in highly purified, monocyte-depleted neutrophil preparations, using selective ligands (TLR2, Pam3CysSerLys4 and Staphylococcus aureus peptidoglycan; TLR4, purified LPS). Activation of either TLR2 or TLR4 caused changes in adhesion molecule expression, respiratory burst (alone, and synergistically with fMLP), and IL-8 generation, which was, in part, dependent upon p38 mitogen-activated protein kinase signaling. Neutrophils also responded to Pam3CysSerLys4 and purified LPS with down-regulation of the chemokine receptor CXCR2 and, to a lesser extent, down-regulation of CXCR1. TLR4 was the principal regulator of neutrophil survival, and TLR2 signals showed relatively less efficacy in preventing constitutive apoptosis over short time courses. TLR4-mediated neutrophil survival depended upon signaling via NF-κB and mitogen-activated protein kinase cascades. Prolonged neutrophil survival required both TLR4 activation and the presence of monocytes. TLR4 activation of monocytes was associated with the release of neutrophil survival factors, which was not evident with TLR2 activation, and TLR2 activation in monocyte/neutrophil cocultures did not prevent late neutrophil apoptosis. Thus, TLRs are important regulators of neutrophil activation and survival, with distinct and separate roles for TLR2 and TLR4 in neutrophil responses. TLR4 signaling presents itself as a pharmacological target that may allow therapeutic modulation of neutrophil survival by direct and indirect mechanisms at sites of inflammation.

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Section: Discussionsupporting

confidence: 79%

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

Sabroe

Prince

Jones

et al. 2003

The Journal of Immunology

305

290

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“…12 Leung et al showed that intraperitoneal injection of IL-18 induced the accumulation of neutrophils in the peritoneal cavity. 13 Our data showed that LPS injection caused an accumulation of neutrophils in the lung associated with thickening of interstitial space and increased MPO activity in WT mice. These neutrophil-related changes were significantly inhibited in IL-18 KO mice, suggesting that the endogenous IL-18 induced accumulation of neutrophils.…”

Section: Discussionmentioning

confidence: 75%

Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

Takahara

Ishikawa

Shuno

et al. 2013

Acute Medicine & Surgery

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Background: Overactivated neutrophils are causes of acute lung injury, which is a major clinical problem with significant morbidity and mortality in sepsis. Serum interleukin (IL)-18 levels correspond to severity of systemic inflammation.Aim: To elucidate the roles of endogenous IL-18 in lung injury during endotoxin-induced systemic inflammation. Methods: Wild-type (WT) and IL-18 gene knockout (KO) mice were injected with lipopolysaccharide (40 mg/kg) intraperitoneally and killed. Lungs were collected at 0 and 12 h to assess mRNA for intercellular adhesion molecule (ICAM)-1, inducible nitric oxide synthase, myeloperoxidase, immunohistochemistry (cleaved caspase-3, 8-hydroxy-2-deoxyguanosine), and wet/dry ratio. Blood was collected at 0, 1, 12, 18, and 24 h to assess plasma cytokine levels. Results:The survival rates at 24 h were approximately 43% and 76% in the WT and KO mice, respectively. Plasma IL-18 levels were induced time-dependently only in the WT mice. Plasma interferon-γ levels were significantly higher in the WT than in the KO mice at 12 h, but IL-6 and tumor necrosis factor-α levels did not differ between the WT and KO mice. At 12 h, the WT mice showed higher myeloperoxidase activity (P < 0.05), ICAM-1, and wet/dry ratios than KO mice. Cleaved caspase-3 positive neutrophils, which migrated in the lung interstitium, were lower in WT mice than in KO mice.Conclusions: Endogenous IL-18 induced neutrophil accumulation, accompanied by induction of ICAM-1 expression, inhibition of neutrophil apoptosis, and increased inducible nitric oxide synthase-induced oxidative tissue injury in the lung, leading to lung edema and poor outcome during endotoxemia.

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“…IL-18 may amplify acute inflammation through promotion of neutrophil adhesion and migration, accompanied by cytokine and chemokine production, and the eventual release of granules. These effects are relevant in vivo because IL-18 administration induces peritoneal neutrophil recruitment (5). In our study, we showed that IL-18 signaling through AcPL is required to up-regulate Mac-1 expression and cytokine production by neutrophils.…”

Section: Discussionmentioning

confidence: 64%

“…Recently, it has also been demonstrated that the function of IL-18 in innate immunity can extend to neutrophil activation. IL-18 therefore may be implicated in inflammatory disorders (5).…”

mentioning

confidence: 99%

Accessory Protein-Like Is Essential for IL-18-Mediated Signaling

Cheung

Chen

Cao

et al. 2005

The Journal of Immunology

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IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18Rα, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18Rα in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN-γ production. In particular, Th1 cells lacking AcPL fail to produce IFN-γ in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling.

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A Role for IL-18 in Neutrophil Activation

Cited by 273 publications

References 44 publications

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

Accessory Protein-Like Is Essential for IL-18-Mediated Signaling

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