1α,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection
Article first published online: 18 DEC 2008
© 2009 Blackwell Publishing Ltd
Volume 127, Issue 4, pages 539–548, August 2009
How to Cite
Coussens, A., Timms, P. M., Boucher, B. J., Venton, T. R., Ashcroft, A. T., Skolimowska, K. H., Newton, S. M., Wilkinson, K. A., Davidson, R. N., Griffiths, C. J., Wilkinson, R. J. and Martineau, A. R. (2009), 1α,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection. Immunology, 127: 539–548. doi: 10.1111/j.1365-2567.2008.03024.x
- Issue published online: 6 JUL 2009
- Article first published online: 18 DEC 2008
- Received 28 September 2008; revised 9 November 2008; accepted 14 November 2008.
- matrix metalloproteinases;
- tissue inhibitors of matrix metalloproteinases;
- vitamin D
Matrix metalloproteinases (MMP) can degrade all components of pulmonary extracellular matrix. Mycobacterium tuberculosis induces production of a number of these enzymes by human macrophages, and these are implicated in the pathogenesis of pulmonary cavitation in tuberculosis. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], has previously been reported to inhibit secretion of MMP-9 in human monocytes (MN), but its influence on the secretion and gene expression of MMP and tissue inhibitors of MMP (TIMP) in M. tuberculosis-infected cells has not previously been investigated. We therefore determined the effects of 1α,25(OH)2D3 on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis-infected human leucocytes; we also investigated the effect of 1α,25(OH)2D3 on the secretion of interleukin-10 (IL-10) and prostaglandin E2 (PGE2), both transcriptional regulators of MMP expression. We found that M. tuberculosis induced expression of MMP-1, MMP-7 and MMP-10 in MN and MMP-1 and MMP-10 in peripheral blood mononuclear cells (PBMC). 1α,25(OH)2D3 significantly attenuated M. tuberculosis-induced increases in expression of MMP-7 and MMP-10, and suppressed secretion of MMP-7 by M. tuberculosis-infected PBMC. MMP-9 gene expression, secretion and activity were significantly inhibited by 1α,25(OH)2D3 irrespective of infection. In contrast, the effects of 1α,25(OH)2D3 on the expression of TIMP-1, TIMP-2 and TIMP-3 and secretion of TIMP-1 and TIMP-2 were small and variable. 1α,25(OH)2D3 also induced secretion of IL-10 and PGE2 from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1α,25(OH)2D3 in M. tuberculosis infection.