Long-chain polyphosphates inhibit type I interferon signaling and augment LPS-induced cytokine secretion in human leukocytes

Abstract

Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate, whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with three different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased LPS-induced IFNβ transcription and secretion, STAT1 phosphorylation, and downregulated subsequent interferon stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented LPS-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling, and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.

The dynamic relationship between inorganic polyphosphate and adenosine triphosphate in human non‐small cell lung cancer H1299 cells

“…Pirttiniemi et al . [ 46 ] found that cells treated with long‐chain polyP (P700) treatment is associated with the activation of mTOR activation in human leukocytes and Wang et al . [ 26 ] reported that polyP stimulates mTOR in mammary cancer cells.…”

Toolkit for cellular studies of mammalian mitochondrial inorganic polyphosphate

“…While the literature is scarce, the toxicity of long chain polyP in mammalian cells has already been suggested by some authors. For example, as previously mentioned, long chains of the polymer induce major effects in the transcriptome, proteome, and phosphatome of mammalian cells (Bondy-Chorney et al, 2020;Pirttiniemi et al, 2023), which could be associated with substantial changes in cell physiology, including viability. Furthermore, it has recently been published that increased release of polyP by astrocytes causes toxicity to motoneurons (Arredondo et al, 2022).…”

“…While the length of mammalian polyP still remains controversial; it has been proposed that this polymer is usually found in two pools in cell lines: very long chains, and short lengths (Kumble and Kornberg, 1995). We decided to use short chains of polyP to conduct all our studies because, based on the bibliography, long chains of the polymer induce major effects in the transcriptome, proteome, and phosphatome of mammalian cells (Bondy-Chorney et al, 2020;Pirttiniemi et al, 2023). Moreover, the data included in this manuscript show that the expression of MitoPPK is lethal for SH-SY5Y cells.…”