Abstract
Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.
Highlights
Accumulating evidence underscores the association and interdependence of hypoxic and inflammatory pathways
In order to investigate the control of IL-6 secretion by CD154 on HK-2 cells, we first assessed the expression and functionality of the CD40, the main receptor of CD154, which localizes at the cell surface after its transport along the secretory pathway
We studied whether CD40 expression was modified by hypoxic conditions
Summary
Accumulating evidence underscores the association and interdependence of hypoxic and inflammatory pathways. Hypoxia can stimulate the expression of proinflammatory cytokines via various pathways, including those involving. Hypoxia pathways drive pro- and anti-inflammatory responses but are regulated, for example, by inflammatory mediators themselves, indicating complex feedback loops in the natural history of inflammation. Acute kidney injury (AKI) is an important example of how inflammatory and hypoxic pathways interdepend. Among the plethora of inflammatory mediators involved, clinical and experimental studies have underscored the contribution of interleukin- (IL-) 6 to renal injury in kidney inflammatory conditions, including AKI [9]. Via the production of inflammatory mediators such as IL-6, tubular epithelial cells (TECs) contribute to AKI-associated inflammation [13]. Coincidental occurrence of inflammation and hypoxia and cross-regulations between hypoxic and inflammatory pathways underline the importance to understand how proinflammatory cytokine expression is regulated under hypoxic conditions. Looking for inhibitors of IL-6 induction by CD154, we examined the potential role of chloroquine, a drug long used in the treatment or prevention of malaria, which has found its application expanded to treat inflammatory diseases [21, 22]
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