Cholecystokinin Inhibits Inducible Nitric Oxide Synthase Expression by Lipopolysaccharide-Stimulated Peritoneal Macrophages

Abstract EN

Cholecystokinin (CCK) was first described as a gastrointestinal hormone.

However, apart from its gastrointestinal effects, studies have described that CCK also plays immunoregulatory roles.

Taking in account the involvement of inducible nitric oxide synthase- (iNOS-) derived NO in the sepsis context, the present study was undertaken to investigate the role of CCK on iNOS expression in LPS-activated peritoneal macrophages.

Our results revealed that CCK reduces NO production and attenuates the iNOS mRNA expression and protein formation.

Furthermore, CCK inhibited the nuclear factor- (NF-) κB pathway reducing IκBα degradation and minor p65-dependent translocation to the nucleus.

Moreover, CCK restored the intracellular cAMP content activating the protein kinase A (PKA) pathway, which resulted in a negative modulatory role on iNOS expression.

In peritoneal macrophages, the CCK-1R expression, but not CCK-2R, was predominant and upregulated by LPS.

The pharmacological studies confirmed that CCK-1R subtype is the major receptor responsible for the biological effects of CCK.

These data suggest an anti-inflammatory role for the peptide CCK in modulating iNOS-derived NO synthesis, possibly controlling the macrophage activation through NF-κB, cAMP-PKA, and CCK-1R pathways.

Based on these findings, CCK could be used as an adjuvant agent to modulate the inflammatory response and prevent systemic complications commonly found during sepsis.