title: Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells.
abstract: Inflammatory cells, such as eosinophils, seem to be key players in the inflammatory process of asthma. These cells are attracted by chemokines, for example eotaxin and monocyte chemotactic protein (MCP-1). In this study, the authors investigated whether eotaxin and MCP-1 expression and release in human airway smooth muscle cells could be modulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. The possible involvement of cAMP-dependent protein kinase A (PKA) was also studied. Forskolin, a direct stimulator of adenylyl cyclase, decreased the interleukin (IL)-1beta-induced eotaxin and MCP-1 release by 73+/-8 and 65+/-6%, respectively. 8Bromo-cAMP, a cAMP analogue, similarly decreased the chemokine production by 58+/-9 and 63+/-8% for eotaxin and MCP-1, respectively. Prostaglandin E2, known as an activator of the prostanoid receptors EP2 and EP4, which are positively coupled to adenylyl cyclase, also decreased the IL-1beta-induced eotaxin and MCP-1 production by 57+/-17 and 53+/-4%, respectively. H-89, an inhibitor of PKA, was able to inhibit the decrease in eotaxin and MCP-1 protein release induced by forskolin. Using Western-blot analysis, no effect of cAMP was found on the IL-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. This study shows that an increase in intracellular cyclic adenosine monophosphate concentration may decrease the interleukin-1beta-induced eotaxin and monocyte chemotactic protein-1 expression and production. This can be inhibited by addition of H-89, an inhibitor of cyclic adenosine monophosphate-dependent protein kinase. No decrease was observed in interleukin-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. These findings may be important for the further development of new anti-inflammatory drugs.
authors.affiliation: Laboratory of Pneumology, Unit of Respiratory Pharmacology, Leuven, Belgium.
authors.forename: W A
authors.initials: WA
authors.lastname: Wuyts
authors.forename: B M
authors.initials: BM
authors.lastname: Vanaudenaerde
authors.forename: L J
authors.initials: LJ
authors.lastname: Dupont
authors.forename: M G
authors.initials: MG
authors.lastname: Demedts
authors.forename: G M
authors.initials: GM
authors.lastname: Verleden
mesh_terms: D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D019742:Chemokines, CC; D007375:Interleukin-1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases