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Published online before print February 24, 2004

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(Journal of Leukocyte Biology. 2004;75:1086-1092.)
© 2004 by Society for Leukocyte Biology

Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis

Department of Infectious Diseases, Faculty of Medicine, Imperial College, Hammersmith Campus, London, United Kingdom

¹ Correspondence: Department of Infectious Diseases, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. E-mail: j.friedland{at}imperial.ac.uk

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 (TNF-) 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- 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- 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 10⁵ 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-.

Key Words: CXCL8 • CCL2 • TNF • IL-1 • networks • gelatinase B

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