Abstract
Tumor necrosis factor (TNF) is best known for inducing a rapid but transient NF-κB-mediated inflammatory response. We investigated later phases of TNF signaling, after the initial transient induction of inflammatory genes has subsided, in primary human macrophages. TNF signaling induced expression of late response genes, including inhibitors of NF-κB and TLR signaling, with delayed and sustained kinetics 6–24 hr after TNF stimulation. A subset of late phase genes was expressed in rheumatoid arthritis synovial macrophages, confirming their expression under chronic inflammatory conditions in vivo. Expression of a subset of late phase genes was mediated by autocrine IL-10, which activated STAT3 with delayed kinetics. Hypoxia, which occurs at sites of infection or inflammation where TNF is expressed, suppressed this IL-10-STAT3 autocrine loop and expression of late phase genes. TNF-induced expression of IL-10 and downstream genes was also dependent on signaling by mTORC1, which senses the metabolic state of cells and is modulated by hypoxia. These results reveal an mTORC1-dependent IL-10-mediated late phase response to TNF by primary human macrophages, and identify suppression of IL-10 responses as a new mechanism by which hypoxia can promote inflammation. Thus, hypoxic and metabolic pathways may modulate TNF responses during chronic inflammation.
Highlights
Tumor necrosis factor (TNF)-α(referred to hereafter as TNF) signals through receptors TNF-R1 and TNF-R2 and initiates a classic pro-inflammatory immune response by activating NF-κB, AP-1, and MAPK1
These genes were selected for study because they were highly expressed in synovial macrophages from rheumatoid arthritis (RA) patients that are chronically exposed to TNF in vivo (Fig. 1B), which confirms their expression under chronic inflammatory conditions in vivo and supports their potentialphysiological importance
Induction of the IL-10-STAT3 loop was dependent on mechanistic target of rapamycin complex 1 (mTORC1), which senses the metabolic state of the cell, providing a connection between macrophage metabolism and the anti-inflammatory IL-10-STAT3 pathway
Summary
TNF-α(referred to hereafter as TNF) signals through receptors TNF-R1 and TNF-R2 and initiates a classic pro-inflammatory immune response by activating NF-κB, AP-1, and MAPK1. Examining pathways regulated by prolonged and sustained exposure to TNF, which we refer to as the “late phase TNF response”, can provide more insight into the complex role of TNF in inflammatory responses and diseases Another key regulator of inflammatory and immune responses is oxygen tension, which varies in vivo, with tissue tension ranging from 2.5–9% O2 but decreasing to levels
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