title: Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha- and interleukin-8 release in human bronchial epithelial cells.
abstract: The cytokine interleukin-17 may play a role in the recruitment of airway neutrophils, and interleukin-17 protein is increased in the airways of patients with asthma. In this study, we characterised the effect of interleukin-17 on the release of the neutrophil-recruiting cytokines granulocyte chemotactic protein (GCP)-2, growth-related oncogene (GRO)-alpha and interleukin-8 in human bronchial epithelial (HBE) cells. We also characterised the involvement of mitogen-activated protein (MAP) kinases as well as the effect of beta-adrenoceptor and glucocorticoid receptor stimulation and calcineurin and P-glycoprotein inhibition on these epithelial responses to interleukin-17. We found that interleukin-17 (1-1000 ng/ml) increased the release of GCP-2, GRO-alpha and interleukin-8 in a concentration-dependent manner. This interleukin-17-induced release of C-X-C chemokines was sensitive to inhibition of the p38 MAP kinase pathway and to stimulation of glucocorticoid receptors. In contrast, stimulation of beta-adrenoceptors increased the release of interleukin-8 and did not markedly alter the release of GCP-2 and GRO-alpha. Inhibition of calcineurin and of P-glycoproteins did not exert any substantial effect on the release of C-X-C chemokines. In conclusion, interleukin-17 bears the potential to increase neutrophil recruitment into the airways by releasing several, different C-X-C chemokines, including GCP-2, GRO-alpha and interleukin-8 in human bronchial epithelial cells. Inhibition of the p38 MAP kinase pathway and glucocorticoid receptor stimulation constitute two credible therapeutic strategies against this interleukin-17-induced release of neutrophil-recruiting cytokines.
authors.affiliation: Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Institute of Internal Medicine, Göteborg University, Guldhedsgatan 10A, 413 46 Göteborg, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Prause
authors.forename: Martti
authors.initials: M
authors.lastname: Laan
authors.forename: Jan
authors.initials: J
authors.lastname: Lötvall
authors.forename: Anders
authors.initials: A
authors.lastname: Lindén
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D065095:Calcineurin Inhibitors; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002461:Cell Line, Transformed; D054360:Chemokine CXCL1; D054427:Chemokine CXCL6; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020381:Interleukin-17 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000318:Adrenergic beta-Agonists; C475829:CXCL1 protein, human; C515503:CXCL6 protein, human; D065095:Calcineurin Inhibitors; D054360:Chemokine CXCL1; D054427:Chemokine CXCL6; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D016209:Interleukin-8; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D011965:Receptors, Glucocorticoid; D016572:Cyclosporine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D000420:Albuterol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D006854:Hydrocortisone