title: Regulation of chemokine gene expression and secretion in Staphylococcus aureus-infected osteoblasts.
abstract: Staphylococcus aureus is the major cause of osteomyelitis or bone infection, leading to major morbidity, often in children. Little is known about immunopathogenesis of osteomyelitis, although uncontrolled inflammation is a major clinical feature. This study investigated effects of dexamethasone, PGE(2) and T(h)2 cytokines, all potential down-regulatory mediators, on control of S. aureus-induced C-X-C (CXCL8, CXCL10) and C-C (CCL5, CCL2) chemokine gene expression and secretion from human osteoblastic MG-63 cells and primary NHOst cells. Chemokine mRNA expression and secretion were reduced 50-75% by dexamethasone, whereas PGE(2) doubled mRNA accumulation, as detected by RNase protection assay and RT-PCR, but decreased chemokine secretion 33-71% (P < 0.05). IL-10 reduced chemokine mRNA accumulation by 20-40% in MG-63 cells. IL-4 and -13 decreased CXCL8 but not CXCL10 gene expression. IL-10 and IL-13 reduced S. aureus-induced osteoblast C-X-C chemokine secretion, whereas IL-4 decreased CXCL8 secretion 2.5-fold and increased CXCL10 secretion 3-fold (all P < 0.05). In contrast, T(h)2 cytokines increased C-C chemokine secretion from MG-63 osteoblastic cells (P < 0.05), and IL-4 and IL-13 caused similar up-regulation of CCL2 secretion from primary osteoblasts. In summary, during S. aureus infection of osteoblasts, T(h)2 cytokines, dexamethasone and PGE(2) have diverse, sometime upregulatory actions on C-C and C-X-C chemokines due to both pre- and post-transcriptional effects on chemokine secretion.
authors.affiliation: Department of Infectious Diseases, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wright
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D018418:Th2 Cells / Q000276:immunology
chemical_list: C111835:CCL2 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D003907:Dexamethasone; D015232:Dinoprostone