Lidocaine modulates interleukin-1β and interferon-α2 secretion in LPS with ATP stimulated human peripheral blood mononuclear cells

Introduction Local anesthetics are canonically used for analgesia and anti-arrhythmic therapy, but increasing evidence indicates additional anti-inflammatory properties, including modulation of purinergic signalling. A recent retrospective observational cohort study indicated that subcutaneous lidocaine–Hydroxypropyl-β-cyclodextrin (HP-β-CD) was associated with sustained improvements in quality of life in patients with neuropathic pain in post-COVID, but the underlying mechanism remains to be established. The aim of this study was to determine whether lidocaine and articaine, alone or in combination with HP-β-CD, modulate in vitro immune cell activation and cytokine secretion in human peripheral blood mononuclear cells (PBMCs). Methods PBMCs were stimulated using phytohemagglutinin (PHA), lipopolysaccharide (LPS), or LPS combined with adenosine triphosphate (ATP) to engage P2X-associated inflammatory pathways, and compounds were applied both prior to and following stimulation. Cytokine secretion was quantified using a 13-plex immunoassay and cell activation was assessed by flow cytometry. Results Lidocaine-containing formulations attenuated cytokine secretion most prominently under conditions engaging ATP-dependent signaling, reducing interleukin-1β and interferon-α2, with interleukin-1β suppression being the most consistent effect across stimulation conditions. Articaine showed less consistent immunomodulatory effects than lidocaine, which may reflect its previously reported lack of purinergic receptor inhibition, while HP-β-CD alone did not influence immune activation or cytokine release under any condition. Discussion Together, these findings show that lidocaine-containing treatments can modulate cytokine responses in human PBMCs, particularly under LPS with ATP stimulation. These findings identify lidocaine as a modulator of ATP-dependent inflammatory signaling.