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.