CD73‐dependent adenosine dampens interleukin‐1β–induced CXCL8 production in gingival fibroblasts: Association with heme oxygenase‐1 and adenosine monophosphate‒activated protein kinase

Abstract

Background During inflammation, stressed or infected cells can release adenosine triphosphate (ATP) to the extracellular medium, which can be hydrolyzed to adenosine by ectonucleotidases such as ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and 5′‐nucleotidase (CD73). The role of CD73 in the modulation of cytokine release by human gingival fibroblasts (HGFs) remains underexplored. Here, we investigated whether CD73‐mediated hydrolysis of extracellular ATP (eATP) could affect interleukin (IL)‐1β‐induced CXCL8 secretion. Methods The levels of mRNA expression of adenosine receptors, CD39 and CD73 of periodontitis samples were retrieved from a public database. Moreover, HGF mRNA levels were measured by quantitative reverse transcription‐polymerase chain reaction (RT‐qPCR) after 3, 6, or 24 hours of IL‐1β stimulation. IL‐1β‐induced CXCL8 protein levels were measured after pretreatment with 100‐µM eATP in the presence or absence of CD73 inhibitor. The effect of eATP degradation to adenosine on CXCL8 levels was investigated using agonist and antagonist of adenosine receptors. Results Levels of CD39, CD73, and adenosine receptor mRNA were differentially modulated by IL‐1β. ATP pretreatment impaired IL‐1β‐induced CXCL8 secretion and required activation of heme oxygenase‐1 (HO‐1) and phosphorylated adenosine monophosphate‒activated protein kinase (pAMPK). The inhibition of CD73 or the inhibition of adenosine receptors abrogated the ATP effect on CXCL8 secretion. Conclusions CD73‐generated adenosine dampens IL‐1β‐induced CXCL8 in HGFs and involves HO‐1 and pAMPK signaling. These results imply that CD73 is a negative regulator of the inflammatory microenvironment, suggesting that this ectoenzyme could be involved in the generation of deficient CXCL8 gradient in chronic inflammation.

CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer

“…IL-1β, another highly enriched chemokine in the TME, plays a crucial role in tumorigenesis and cancer progression. 36 Several studies have shown that IL-1β can induce CXCL8 expression and secretion, 37,38 which further promotes tumor progression in triple-negative breast cancer. 39 However, the relationship between IL-1β and the expression of CXCL8 in CRC TME has not been verified.…”

Purinergic Signaling in Oral Tissues

“…Adenosine also inhibited the action of pro-inflammatory chemokines such as CXCL8, which plays a central role in the inflammatory response driven by periodontal infection. Interestingly, adenosine effect was mediated by an increased activity of the intracellular hemeoxygenase-1 and adenosine monophosphate-activated protein kinase (AMPK), both being key regulators of the host inflammatory responses [ 115 ]. Furthermore, studies on A 2A R have demonstrated that their stimulation may be used to induce replication of P. gingivalis in GECs [ 116 ], which may have a protective effect, as above reported.…”

Selective Antimicrobial Therapies for Periodontitis: Win the “Battle and the War”

“…In parallel, but not at odds with this hypothesis [ 83 ], is the notion that unresolved inflammation, especially neutrophil-mediated, is the principal driving force for pathogenesis (reviewed in [ 84 ]). This notion has received considerable attention of late, involving novel therapeutic approaches targeting neutrophil emigration and clearance through manipulation of CXCL8 [ 85 , 86 , 87 ] or applying pre-resolving mediators. The latter include resolvins, protectins, maresins, and lipoxins.…”