The Organogermanium Compound 3-(trihydroxygermyl)propanoic Acid Exerts Anti-Inflammatory Effects via Adenosine-NR4A2 Signaling

We previously reported that 3-(trihydroxygermyl)propanoic acid (THGP) suppresses inflammasome activation in THP-1 cells following stimulation with lipopolysaccharide (LPS) and ATP (signals 1 and 2) by forming a complex with ATP, thereby inhibiting IL-1β secretion. Our findings also suggested that THGP inhibits inflammasome activation through mechanisms independent of ATP complex formation. This study investigated the anti-inflammatory effects of THGP on signal 1 (ATP-independent) of inflammasome activation. THGP suppressed NF-κB nuclear translocation in LPS-stimulated THP-1 cells, which reduced the mRNA expression of the proinflammatory cytokines TNF-α and IL-6, as well as IL-1β secretion. This mechanism was mediated by the formation of a THGP-adenosine complex, which inhibited adenosine degradation and subsequently activated adenosine-NR4A2 signaling. Thus, THGP exerts anti-inflammatory effects by forming a complex with adenosine, leading to adenosine-NR4A2 signaling pathway activation. This mechanism is distinct from the ATP-dependent pathway by which THGP was previously reported to function. By targeting both ATP-dependent and ATP-independent inflammasome activation pathways, THGP has potential as a broad-spectrum therapeutic agent for various inflammatory diseases.