IL-1 regulates in vivo C—X—C chemokine induction and neutrophil sequestration following endotoxemia

The significance of bacterial RNA recognition for initiating innate immune responses against invading pathogens has only recently started to be elucidated. Bacterial RNA is an important trigger of inflammasome activation, resulting in caspase-1–dependent cleavage of pro–IL-1β into the active form. It was reported previously that prolonged treatment with IFN-γ can inhibit IL-1β production at the level of both transcription and Nlrp3 inflammasome activation in an NO-dependent manner. As a result of the delayed kinetics of NO generation after IFN-γ stimulation, these effects were only observed at later time points. We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages and dendritic cells by an additional, very rapid mechanism that was independent of NO. Costimulation with IFN-γ selectively attenuated binding of NF-κB p65 to the IL-1β promoter, thus representing a novel mechanism of IL-1β inhibition by IFN-γ. Transcriptional silencing was specific for IL-1β because expression of other proinflammatory cytokines, such as TNF, IL-6, and IL-12p40, was not affected. Furthermore, by suppressing IL-1β production, IFN-γ impaired differentiation of Th17 cells and production of neutrophil chemotactic factor CXCL1 in vitro. The findings provide evidence for a rapid immune-modulating effect of IFN-γ independent of NO.

Section: Discussionmentioning

confidence: 99%

Early Inhibition of IL-1β Expression by IFN-γ Is Mediated by Impaired Binding of NF-κB to the IL-1β Promoter but Is Independent of Nitric Oxide

Eigenbrod

Bode

Dalpke

2013

“…However, blocking IL-1 activity is not without its drawbacks. For example, treatment with anakinra, anti-IL-1b (canakinumab) or monoclonal anti-IL-1R1 Abs can result in neutropenia (16) and an increased risk of infections (17)(18)(19). Anakinra is contraindicated in immune-compromised patients and in patients with a history of recurrent infections.…”

Section: Discussionmentioning

confidence: 99%

IL-1 Receptor Antagonist Chimeric Protein: Context-Specific and Inflammation-Restricted Activation

Rider

Carmi

Yossef

et al. 2015

Self Cite

Both IL-1α and IL-1β are highly inflammatory cytokines mediating a wide spectrum of diseases. A recombinant form of the naturally occurring IL-1R antagonist (IL-1Ra), which blocks IL-1R1, is broadly used to treat autoimmune and autoinflammatory diseases; however, blocking IL-1 increases the risk of infection. In this study, we describe the development of a novel form of recombinant IL-1Ra, termed chimeric IL-1Ra. This molecule is a fusion of the N-terminal peptide of IL-1β and IL-1Ra, resulting in inactive IL-1Ra. Because the IL-1β N-terminal peptide contains several protease sites clustered around the caspase-1 site, local proteases at sites of inflammation can cleave chimeric IL-1Ra and turn IL-1Ra active. We demonstrate that chimeric IL-1Ra reduces IL-1–mediated inflammation in vitro and in vivo. This unique approach limits IL-1 receptor blockade to sites of inflammation, while sparing a multitude of desired IL-1–related activities, including host defense against infections and IL-1–mediated repair.

“…How IL-1 in normal infected mice causes PMN influx remains unclear. However, because IL-1 itself is not chemotactic for PMN (31), the effect must be indirect, with IL-1 inducing one or more chemokines. A likely candidate is MIP-2, because MIP-2-neutralized mice develop minimal PMN responses to ocular HSV infection (30).…”

Section: Discussionmentioning

confidence: 99%

Mice Transgenic for IL-1 Receptor Antagonist Protein Are Resistant to Herpetic Stromal Keratitis: Possible Role for IL-1 in Herpetic Stromal Keratitis Pathogenesis

Biswas

Banerjee

Kim

et al. 2004

Ocular infection with HSV may result in the blinding immunoinflammatory lesion stromal keratitis (SK). This represents a CD4+ T cell-mediated immunopathologic lesion in both humans and a mouse model. Early events in the pathogenesis that set the stage for SK are poorly understood. The present study evaluates the role of IL-1 using a transgenic mouse that overexpresses the IL-1 receptor antagonist (IL-1ra) protein. Such transgenic mice were markedly resistant to SK compared with IL-1ra−/− and C57BL/6 control animals. The resistance was shown to be the consequence of reduced expression of molecules such as IL-6, macrophage-inflammatory protein-2, and vascular endothelial growth factor, normally up-regulated directly or indirectly by IL-1. A critical event impaired in IL-1ra transgenic mice was vascular endothelial growth factor production with a consequent marked reduction in angiogenesis, an essential step in SK pathogenesis. Targeting IL-1 could prove to be a worthwhile therapeutic approach to control SK, an important cause of human blindness.