期刊
IMMUNOLOGY
卷 127, 期 4, 页码 539-548出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1365-2567.2008.03024.x
关键词
interleukin-10; matrix metalloproteinases; mycobacteria; TB; tissue inhibitors of matrix metalloproteinases; vitamin D
类别
资金
- British Lung Foundation [TB05/11]
- Wellcome Trust [064261, 072070]
- Northwick Park Hospital Tropical Research Fund
- Medical Research Council [MC_U117588499] Funding Source: researchfish
- MRC [MC_U117588499] Funding Source: UKRI
P>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, 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3], 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 1 alpha,25(OH)(2)D-3 on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis-infected human leucocytes; we also investigated the effect of 1 alpha,25(OH)(2)D-3 on the secretion of interleukin-10 (IL-10) and prostaglandin E-2 (PGE(2)), 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). 1 alpha,25(OH)(2)D-3 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 1 alpha,25(OH)(2)D-3 irrespective of infection. In contrast, the effects of 1 alpha,25(OH)(2)D-3 on the expression of TIMP-1, TIMP-2 and TIMP-3 and secretion of TIMP-1 and TIMP-2 were small and variable. 1 alpha,25(OH)(2)D-3 also induced secretion of IL-10 and PGE(2) from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1 alpha,25(OH)(2)D-3 in M. tuberculosis infection.
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