This study explores the role of hyperpolarization-activated cyclic nucleotide-gated HCN channels in macrophage inflammation and their potential impact on intestinal motility. While HCN2 inhibition is known to decrease intestinal motility, its involvement in the development of ileus remains unclear. The research focused on HCN channels, particularly HCN2, which are crucial for cellular excitability and pacemaking, and are now recognized for their role in immune modulation. THP1 cells were treated with the HCN channel blocker ZD7288 or a vehicle control (DMSO) and subjected to cyclic stretch, with cytokine release measured to assess inflammation. Using the FlexCell system to apply mechanical stretch to activated THP1 cells, results showed a significant reduction in macrophage cytokine release following HCN2 inhibition. These findings enhance our understanding of HCN2 channels in macrophage inflammation and suggest their potential as therapeutic targets.