title: CCK-8 inhibits LPS-induced IL-1beta production in pulmonary interstitial macrophages by modulating PKA, p38, and NF-kappaB pathway.
abstract: The neuropeptide cholecystokinin octapeptide (CCK-8) inhibits inflammation by downregulating the expression of proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin (IL) 1beta during endotoxin shock. However, the signaling mechanism of CCK-8 action has not yet been clearly elucidated. In this study, we have examined the possible signaling pathways by which CCK-8 inhibits lipopolysaccharide (LPS)-induced IL-1beta production in rat pulmonary interstitial macrophages. In macrophages, LPS is known to activate p38 kinase, which, in turn, activates nuclear factor (NF)-kappaB to induce IL-1beta production. We found that the pretreatment of cells with CCK-8 blocked the LPS-induced p38 kinase, NF-kappaB activation, and IL-1beta production. Furthermore, CCK-8 treatment activated the cyclic adenosine monophosphate-protein kinase A signaling pathway and H-89 (a protein kinase A inhibitor), abrogated the inhibitory effects of CCK-8 on p38 kinase activation and NF-kappaB activation. In addition, we also demonstrate that the specific antagonist to CCK-1 receptor (CCK-1R) and CCK-2 receptor (CCK-2R) abrogate the CCK action, and that the effects of the antagonist specific to CCK-1R is more significant. These results suggest that these responses were mediated through CCK-1R and CCK-2R, and CCK-1R might be the major receptor responsible for the anti-inflammatory effect of CCK-8. Taken together, our results indicate that the stimulation of cyclic adenosine monophosphate-protein kinase A signaling pathway by CCK-8 through CCK-1R and CCK-2R inhibits the LPS-induced activation of p38 kinase and NF-kappaB to block the IL-1beta production in rat pulmonary interstitial macrophages.
authors.affiliation: Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Shujin
authors.initials: S
authors.lastname: Li
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Ni
authors.forename: Bin
authors.initials: B
authors.lastname: Cong
authors.forename: Weijuan
authors.initials: W
authors.lastname: Gao
authors.forename: Shunjiang
authors.initials: S
authors.lastname: Xu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Yao
authors.forename: Chunling
authors.initials: C
authors.lastname: Ma
authors.forename: Yiling
authors.initials: Y
authors.lastname: Ling
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D002766:Cholecystokinin; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012844:Sincalide