Cholecystokinin inhibits inducible nitric oxide synthase expression by lipopolysaccharide-stimulated peritoneal macrophages.

Abstract

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.

• Authors: Rafael Simone Saia, Fabíola Leslie Mestriner, Giuliana Bertozi, Fernando Queiróz Cunha, Evelin Capellari Cárnio
• Journal: Mediators of inflammation (Mediators Inflamm) Vol. 2014 Pg. 896029 ( 2014) ISSN: 1466-1861 [Electronic] United States
• PMID: 25125801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Lipopolysaccharides
• NF-kappa B
• Nitric Oxide
• Cholecystokinin
• Nitric Oxide Synthase Type II

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cholecystokinin (pharmacology)
• Lipopolysaccharides (pharmacology)
• Macrophages, Peritoneal (drug effects, metabolism)
• Male
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)