Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis.
Tuberculous osteomyelitis causes bony destruction as a result of interactions among the pathogen, resident bone cells, and influxing leukocytes. Recruitment of monocytes and T cells is critical for antimycobacterial granuloma formation, but little is known about mechanisms regulating this in bone. We investigated the role of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1, key cytokines in granuloma formation, in networks involving human osteoblasts and monocytes. Experiments focused on CXC ligand (CXCL)8, CCL2, and matrix metalloproteinase (MMP)-9, human monocyte-derived mediators involved in control of leukocyte influx. TNF-alpha but not IL-1 has a key role stimulating CXCL8 secretion in Mycobacterium tuberculosis-infected human osteoblast MG-63 cells. Conditioned medium from M. tuberculosis-infected osteoblasts (COBTB) drives CXCL8 and some CCL2 gene expression and secretion from primary human monocytes. IL-1 receptor antagonist and to a lesser extent anti-TNF-alpha inhibited COBTB-induced CXCL8 secretion (P<0.01) but did not affect gene expression. IL-1 blockade had a comparatively lesser effect on CCL2 secretion, whereas anti-TNF decreased CCL2 concentrations from 7840 +/- 140 to 360 +/- 80 pg/ml/4 x 10(5) cells. Neither proinflammatory mediator affects MMP-9 secretion from COBTB-stimulated human monocytes. In summary, in a paracrine network, M. tuberculosis-infected osteoblasts drive high-level CXCL8, comparatively less CCL2, but do not alter MMP-9 secretion from uninfected human monocytes. This network is, in part, regulated by IL-1 and TNF-alpha.
Department of Infectious Diseases, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
Kathleen M
KM
Wright
Jon S
JS
Friedland
D002478:Cells, Cultured; D018932:Chemokine CCL2; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D017077:Culture Media, Conditioned; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010019:Osteomyelitis / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D014394:Tuberculosis, Osteoarticular / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D019743:Chemokines, CXC; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D011506:Proteins; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9