The Rate of Interleukin-1β Secretion in Different Myeloid Cells Varies with the Extent of Redox Response to Toll-like Receptor Triggering

Abstract

Human myeloid cells activate the NLRP3 inflammasome and secrete interleukin (IL)-1β in response to various Toll-like receptor (TLR) ligands, but the rate of secretion is much higher in primary human monocytes than in cultured macrophages or THP-1 cells. The different myeloid cells also display different redox status under resting conditions and redox response to TLR activation. Resting monocytes display a balanced redox state, with low production of reactive oxygen species (ROS) and antioxidants. TLR engagement induces an effective redox response with increased ROS generation followed by a sustained antioxidant response, parallelled by efficient IL-1β secretion. Drugs blocking ROS production or the antioxidant response prevent the secretion of mature IL-1β but not the biosynthesis of pro-IL-1β, indicating that redox remodeling is responsible for IL-1β processing and release. Unlike monocytes, THP-1 cells and cultured macrophages have up-regulated antioxidant systems that buffer the oxidative hit provided by TLR triggering and suppress the consequent redox response. This aborted redox remodeling is paralleled by low efficiency IL-1β processing and secretion. High doses (5 mm) of H2O2 overcome the high antioxidant capacity of THP-1 cells, restore an efficient redox response, and increase the rate of IL-1β secretion. Together these data indicate that a tightly controlled redox homeostasis in resting cells is a prerequisite for a robust redox response to TLR ligands, in turn necessary for the efficient inflammasome activation. Inflammasome activation by bacterial DNA is not modulated by redox responses, suggesting that redox-dependent regulation of IL-1β secretion is restricted to some inflammasomes including NLRP3 but excluding AIM-2.

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

“…However, a combination of both the TLR2 and TLR4 Abs at the same concentration was able to completely inhibit the production of IL-10 in these cells. This could possibly be due to the fact that THP-1 is a monocyte/macrophage tumor cell line known to respond differently when compared with the primary macrophages (80,81). Therefore, it is possible that in the PMA-differentiated THP-1 macrophages, downstream TLR signaling pathways may not be as tightly regulated as in the primary macrophages.…”

NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

“…These contrasting findings might be due to differences in the mechanisms involved in the exportation of IL-1β out of the cell between mononuclear phagocytes and neutrophils, an issue that deserves further investigation. Previous work in monocytes showed that diphenyliodonium, a NADPH oxidase inhibitor, reduced IL-1β secretion [33,34]. These studies suggested that ROS generated upon TLR stimulation trigger an antioxidant response that is ultimately required for IL-1β secretion.…”

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

“…The difference in IL1␤ production with PMA treatment cannot be attributed to PMA alone, as PMA treatment does not increase IL1␤ levels (Ref. 53 and data not shown). TNF␣ and IL-6 cytokine responses are also concordant in the contrast between strains, similar to previously published data for IL-8 (29), further establishing that the U112 and LVS strains differ in their capacity to stimulate proinflammatory cytokines.…”

“…For example, the nucleotide binding domain-leucine-rich repeat region of NLRP3 differs from Nlrp3 in the distribution of potential serine/threonine phosphorylation sites, oxidant-sensitive cysteine residues, charged residues, and lysines that may serve as ubiquitination sites (data not shown). However, our results cannot rule in a critical function difference based on amino acid sequence, thus both the possible contribution of specific residues and potential differences acting in an indirect fashion such as species differences in reactive oxygen generation (53,57). Sensitivity to apoptotic/pyroptotic death signals and potential ligand adapter proteins (58) should be considered.…”