Neutrophil-mediated inhibition of proinflammatory cytokine responses
SourceJournal of Immunology, 189, 10, (2012), pp. 4806-15
Article / Letter to editor
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Journal of Immunology
SubjectIGMD 5: Health aging / healthy living N4i 1: Pathogenesis and modulation of inflammation; N4i 1: Pathogenesis and modulation of inflammation; N4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunity; N4i 2: Invasive mycoses and compromised host; N4i 2: Invasive mycoses and compromised host
Neutrophils (polymorphonuclear neutrophils [PMNs]) play an elaborate role in the innate immune response against invading pathogens. Recent research provided evidence that PMNs can play a modulatory role in inflammation next to their primary role of phagocytosis. In the current study, we investigated whether neutrophils can modulate the innate immune response against Candida albicans. Production of the proinflammatory cytokines IL-1beta and TNF-alpha by human PBMCs in response to C. albicans or LPS was decreased by coculture of PMNs; however, the anti-inflammatory cytokine IL-10 remained unaffected. Using Transwells and cells of patients with chronic granulomatous disease, we show that this downregulation of proinflammatory cytokine production was independent of phagocytosis and reactive oxygen species but was dependent on a soluble factor. We suggest that neutrophil-derived proteases are responsible for the downregulation of IL-1beta and TNF-alpha, as cytokine production could be recovered by addition of alpha1-antitrypsin, an endogenous inhibitor of serine proteases. PMN lysates and neutrophil elastase could degrade recombinant human IL-1beta and TNF-alpha but not IL-10, and this could be inhibited by addition of alpha1-antitrypsin. Moreover, we also provide evidence that the dampening effect of PMNs is present in vivo in a murine zymosan-induced arthritis model and a murine experimental endotoxemia model. Altogether, our data show that PMNs can dampen the proinflammatory response to C. albicans by protease-mediated degradation of cytokines. This observation suggest that PMNs might play a important regulatory role in the host defense against C. albicans and can be important for understanding the regulation of inflammation in general.
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