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Published online before print November 1, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0806512

Received for publication August 10, 2006.
Revised September 19, 2006.
Accepted for publication October 5, 2006.

Article

Monocytes infected with Mycobacterium tuberculosis regulate MAP kinase-dependent astrocyte MMP-9 secretion

Department of Infectious Diseases & Immunity, Imperial College, Hammersmith Campus, London, United Kingdom

^@ To whom correspondence should be addressed. E-mail: j.friedland{at}imperial.ac.uk.

	Abstract

Tuberculosis (TB) of the CNS (CNS-TB) carries a high mortality. Disease pathology is characterized by widespread destruction of CNS tissues. Matrix metalloproteinase-9 (MMP-9) is able to catabolyze specific components of the CNS tissue matrix and blood-brain barrier. Increased cerebrospinal fluid MMP-9 concentrations are associated with tissue damage, leukocyte infiltration, and death in CNS-TB. Using zymography, Western analysis, and transcription factor assays, we investigated mechanisms regulating MMP-9 activity in CNS-TB. We demonstrate that conditioned media from monocytes infected with Mycobacterium tuberculosis (CoMTB) induce MMP-9 secretion from astrocytes (U373-MG). IL-1 and TNF- are necessary but not sufficient for such induction of astrocyte MMP-9 secretion. CoMTB up-regulates AP-1 DNA-binding activity, and the c-Jun, FosB, and JunB subunits are particularly increased. MMP-9 secretion from CoMTB-stimulated astrocytes is dependent on the activity of p38, Erk, and Jnk MAPKs. Phosphorylation of p38, Erk, and Jnk is activated rapidly, peaking 30 min poststimulation with CoMTB. Inhibition of IL-1 but not TNF- in CoMTB decreases p38, Erk, and Jnk activity in astrocytes. Consistently, IL-1 signals through the MAPK cascade at physiological levels, whereas TNF-, IL-6, IL-10, CCL-2, CCL-5, and CXCL-8 (all present in CoMTB) do not. In summary, the data suggest that monocyte-dependent cytokine networks may play a key role in the development of a matrix-degrading environment during CNS-TB.

Key Words: gelatinase B • IL-1 • TNF-